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Current Developments of Coumarin Compounds in Medicinal Chemistry

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3884 Current Pharmaceutical Design, 2013, 19, 3884-3930

Current Developments of Coumarin Compounds in Medicinal Chemistry

Xin-Mei Peng, Guri L.V. Damu# and Cheng-He Zhou*

Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing
400715, People’s Republic of China

Abstract: Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with
typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of en-
zymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some
coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing
supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been
actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing
quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate
pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medici-
nal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative,
antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive
agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design
strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarin-
based medicinal chemistry are also presented.

Keywords: Antibacterial, anticancer, anticoagulant, antioxidative, biological stain, coumarin, probe, supramolecular drug.

1. INTRODUCTION pharmacokinetic properties in the biologically detective techniques.

Coumarin compounds are a large class of quite important lac-
tones with a fused structure of benzene ring and
-pyrone, and
virtually contain - conjugated system with rich electron and good
charge-transport properties. This kind of rigid fused ring endues
coumarin-based derivatives with wide potential applications in the
fields of bromatology, material and supramolecular chemistry as
well as medicinal chemistry. Specially, coumarin compounds as
medicinal drugs have been increasingly attracting special interest
due to their potential outstanding contributions in the prevention
and treatment of diseases, and the related researches and develop-
ments have become an extremely attractive highlight [1-3]. Cou-
marin compounds have latent ability to exert noncovalent interac-
tions (hydrophobic, - and electrostatic interactions as well as
hydrogen bonds, metal coordination, van der Waals force etc.) with
the various active sites in organisms, and thus display a wide range
of biological activities such as anticoagulant [4], antineurodegen-
erative [5], antioxidant [6], anticancer [7] and antimicrobial [8]
efficacies and so on. Moreover, the oxygen-containing coumarin
scaffold with unique characteristic is also considered as a kind of
ideal block to produce supramolecular assembly with interesting
molecules and ions including bioactive species, thus is frequently
employed in the rational design and construction of supramolecular
medicinal agents [9], particularly in antibacterial and antifungal
fields which have shown preliminary application prospect and at-
tracted much attention in recent years. More importantly, the excel-
lent fluorescent capacities of coumarin compounds [10] resulting
from the electron-rich and good charge-transport properties of -
conjugated system provide their underlying development value as
artificial ion receptors, fluorescent probes for biologically important
species and biological stains to monitor timely enzyme activity,
complex biological events as well as accurate pharmacological and
*Address correspondence to this author at the Laboratory of Bioorganic &
Medicinal Chemistry, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing, 400715, People’s Republic of China;
Tel:/Fax: +86-23-68254967; E-mail: zhouch@swu.edu.cn
#Postdoctoral fellow from Indian Institute of Chemical Technology (IICT),
India
It is reasonable that coumarin backbone is prevalently applied to
construct diverse functional molecules for biological diagnosis and
probes. A great deal of work has been directed not only towards the
separation and purification of naturally occurring biological cou-
marins from a variety of plants, animals and microorganisms, but
also towards the developments of artificial synthetic coumarin
compounds with novel structures and properties. Particularly, cou-
marin-based bioactive molecules as new drugs have been exten-
sively investigated and some of them like anticoagulant warfarin 1a
have been marketed and extensively used in clinic. More impor-
tantly, a lot of coumarin compounds as medicinal candidates with
strong pharmacological activity, low toxic and side-effect, little
drug resistance, high bioavailability, broad spectrum and good cura-
tive effects are being actively developed. On the other hand, a large
number of increasing researches are focusing on the application
developments of coumarin-based diagnostic agents and pathologic
probes for probing pathological and pharmacological mechanism.
This has gradually become an active new trend in coumarin me-
dicinal chemistry. All the mentions above have strongly pointed out
an infinite space for the extensively potential application and large
development value of coumarin compounds. However, so far no
comprehensive report of coumarins in the whole rang of medicinal
chemistry has been observed. This review thus provides for the first
time a systematic summary and insight of coumarin compounds in
medicinal chemistry as anticoagulant, antineurodegenerative, anti-
cancer, antioxidative, antibacterial, antifungal, antivirus, antipara-
sitic, antiinflammatory and analgesic, antidiabetic, antidepressive
and other bioactive agents as well as supramolecular medicinal
drugs, artificial ion receptors, fluorescent probes for biologically
important chemical species and biological stains. It is expected that
this review is helpful for the rational designs and successful studies
of coumarin-derived medicinal drugs as well as for the effective
developments of coumarin-based diagnostic agents and pathologic
probes for their applications in biological system.
2. ANTICOAGULANT COMPOUNDS
Thrombotic events have become a severe threat to human
health and caused high mortality in recent years. A lot of effort has

/13 $58.00+.00 © 2013 Bentham Science Publishers

Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3885

been made to discover antithrombotic compounds [11]. Current
anticoagulant drugs are usually used to prevent the expansion of
blood clots in phlebitis or deep vein thrombosis, and treat intravas-
cular embolism, thrombosis, stroke and other thrombotic, and as
prophylactic agents in patients that have mechanical heart valves
diseases. The prevalent clinical anticoagulant drugs are non-
intestinal anticoagulant agents (e.g. heparin), antiplatelet aggrega-
tion drugs (e.g. aspirin), and vitamin K antagonists (e.g. warfarin).
Coumarin com-pounds like warfarin (1a), acenocoumarol (1b),
cyclocumarol (2) and dicoumarol (3) as anticoagulant drugs have
been widely used as essential oral anticoagulant agents for near half
century. Specially, warfarin is the most extensive one of clinical
anti-coagulant coumarin worldwide due to its fast and complete
absorption in the gastrointestinal tract [12,13]. However, coumarin-
based anticoagulant drugs in clinic are limited because of narrow
therapeutic range and patients are at risk of over or under antico-
agulation which are dependent on several environmental and clini-
cal factors including concurrent medication, diet, age and genotype
for polymorphisms in CYP2C9 and VKORC1 [14,15]. These short-
comings inspire numerous researchers to devote to their studies for
new alternative anticoagulant agents with broad therapeutic range
and little secondary effect [16].
Novel anticoagulant compounds that are structurally different
from existing clinical drugs have received increasing attention.
Acetamido-substituted coumarin 4a was found to be the suitable
substrate of platelet calreticulin transacetylase, which might be
related to the enhancement of NO level in blood platelets [17]. Fur-
ther study indicated that the 7-N-acetylamino group in coumarin
skeleton exerted a crucial influence in enhancing the specificity of
platelet calreticulin transacetylase. Acetoxy-substituted coumarin
4b could effectively inhibit platelet aggregation [18]. Its activity
would be decreased by the substitution of bulky alkyl groups at C-3
position due to the steric hindrance of the acetoxy substrates to
access the active site of calreticulin transacetylase. The car-
boxyethyl coumarin 5 was a highly active compound with
prothrombin time (PT) value of 30.0 s and in vivo low or non-toxic
effect [19]. Structure-activity relationship manifested that the car-
boxyl group in cis-position played an important role in exerting
anticoagulant potency. Molecular docking and mechanistic studies
revealed that the 4-hydroxyl group in the form of phenolic anion
could effectively interact with the Cys135 catalytic site in the tran-
sition state.
Pyrazole ring with five-membered nitrogen heterocyclic struc-
ture is an important fragment for bioactivity. Some pyrazole modi-
fied molecules have been found to possess antithrombotic action.
The hybridization of 4-hydroxycoumarin with substituted pyrazole
ring yielded compound 6. It was in vitro active against blood co-
agulation with 19.4% relative potency in relation to warfarin. In
vivo anticoagulant test showed that derivative 6 exerted a remarka-
bly prolonged prothrombin time (PT = 3.5 min) with anticoagulant
value similar to that of warfarin (PT = 4.4 min). Structure-activity
relationship revealed that the replacement of phenylcarbothioamido
moiety at 1-position of the pyrazolyl moiety by carbothioamido,
acetyl or phenyl one as well as the removal of C-5 pyridine ring
resulted in the loss of the anticoagulant effect [20].
Recently, the activated factor XII (FXIIa) has become an origi-
nal and attractive target for the development of new anticoagulant
drugs with low rates of therapy-related hemorrhages despite of its
limited effects on hemostasis. The halogen substituted coumarins
7a and 7b were identified as promising FXIIa inhibitors with IC50
(50% inhibitory concentration) values of 4.30 and 4.40 μM respec-
tively in comparison to D-Pro-Phe-Arg chloromethyl ketone (IC50 =
0.18 μM). Further studies suggested that the two compounds could
act as mechanism-based inhibitors of FXIIa through the formation
of an acyl enzyme. Interestingly, for 8-chloro substituted coumarin
7a, the introduction of methyl group was favorable, while for 8-
bromo coumarin 7b, the introduction of methyl substituent led to a
decrease of inhibitory potency [21]. Coumarin 8 was also found to
show anticoagulant activity. However, it still produced significant
increase in bleeding time (144 s) in comparison with standard drug
warfarin (190 s), and the action mechanism was not clear [22].
With the emergence of hemorrhages for majority of patients
after administration of coumarin anticoagulants, a lot of workers
have transferred much attention to the detailed pharmacologic and
toxicologic properties of coumarin-based anticoagulants in recent
years.

O
H3C O
OH CH3 CH3
O OH OH

O O R
O O O OO O
1a: R = H Warfarin
1b: R = NO2 Acenocoumarol 2 Cyclocumarol 3 Dicoumarol

CH3
OH CH3
R
O COOCH2CH3

H3C X O O COOCH2CH3
4a: X = NH, R = H 4b: X = O, R = n-C3H7 O O 5

O
N
O NH
Cl Cl
N OH
OH H R2
H H3C CH3
N N
O O
N H3C O O 8
S R1 7a: R1 = Cl, R2 = 3,5-CH3
O O 6 7b: R1 = Br, R2 = H
3886 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
CH3
N O CH3
H3C
N 3
OCH3
H3CO O O
9 Ensaculin
3. ANTINEURODEGENERATIVE COMPOUNDS
Neurodegeneration is a large class of chronic and progressive
nervous system diseases based on constitutional neuronal degenera-
tion, including Alzheimer’s disease (AD), Parkinson’s disease
(PD), Huntington disease and amyotrophic lateralsclerosis and so
on. Though the pathological characteristic and the cause of these
diseases are different, all these diseases present the degeneration of
nervous cells. AD and PD are the most common neurodegenerative
disease in the elderly, which severely influence their life quality.
Fortunately, some studies have preliminarily demonstrated the
dominance of coumarin compounds in the treatment of AD and PD.
3.1. Coumarin Compounds as Medicinal Agents for Anti-
Alzheimer’s Disease
AD is a neurodegenerative disorder, has become the most
common cause of dementia among the elderly and an increasingly
severe medical and social problem with the rapid growth of aging
people in industrialized and some developing countries. AD is rele-
vant to inflammation,  protein aggregation, amyloid-
protein
(A
) deposits, oxidative stress, and dysfunction of acetylcholine
signaling in the basal forebrain. Researches for development of
chemical agents to cure AD have been attracting large interest for
many years [23-26].
Acetylcholinesterase (AChE) is a predominant enzyme in mus-
cle and nervous system, which plays a fundamental role in impulse
transmission by terminating the action of neurotransmitter acetyl-
choline at cholinergic synapses and neuromuscular junctions.
Ensaculin 9 is a well-known coumarin AChE inhibitor, which has
been used clinically as its hydrochloride with trade name of muri-
atic KA-672 in treating AD for a long time. Structural modification
of compound 9 yielded its analog 10 with an expected anti-AChE
efficacy. Compared to reference drug donepezil (IC50 = 0.11 μM),
compound 10 still exhibited promising AChE inhibitory potentiality
in spite of having a higher IC50 value of 4.50 μM [27]. Further stud-
ies suggested that the phenylpiperazine substitution at the C-4 posi-
tion should make a positive contribution to bioactivity, and the
distance between carbonyl-carbon atom and nitrogen atom of
piperazine ring was important. Moreover, the nitrogen atom from
the phenylpiperazine groups could interact with the catalytic center
of AChE, and the phenyl ring connecting with the piperazine ring
was able to act as the choline binding site. However, 6-substituted
coumarins did not show anti-AChE activity.
Piperidyl coumarin 11 was also identified to be a potential
AChE inhibitor with 85% inhibitory rate at 200 μM. It gave an IC50
value of 6.35 μM, which was superior to standard drug gal-
anthamine (IC50 = 12.68 μM) [28]. The result manifested that the
introduction of piperidyl group was favorable for improving inhibi-
tory activity. Mechanistic studies indicated that compound 11 ex-
OH CH3
H3C
N O n
O O
H3C I
12a: n = 3 12b: n = 4
CH3
Peng et al.
N
H3C O
N
N
O
O O O O O
10 11
erted a competitive mechanism of action with Ki value of 2.67 μM.
Undoubtedly, coumarin 11 is worthy to be further investigated.
Quaternary ammonium salts 12a and 12b containing edropho-
nium-like cationic moiety showed strong AChE affinity with IC50
values of 2.10 and 1.00 nM, respectively, and good AChE selectiv-
ity with selective index (SI) values of 505 and 708. Particularly, the
AChE inhibitory activity of compound 12b was 12,000- and
42,000-fold higher than that of 3-hydroxy-N,N,N-trimethylbenzena-
minium iodide (3-HBT) and 3,4-dimethyl-7-methoxycoumarin res-
pectively [29]. The impressive AChE affinity likely resulted from
the strong interactions between both coumarin and 3-HBT moieties
respectively and the peripheral anionic and catalytic binding sites.
The structural feature of quaternary ammonium salts 12a-b,
which showed desirable anti-AChE activities, prompted a continu-
ous investigation towards structurally similar compounds in order
to discover new entities with therapeutic potentiality. Analog 13
exhibited more excellent AChE affinity (IC50 = 0.23 nM) and selec-
tivity (SI > 300000) than reference drug donepezil (IC50 = 5.33
nM), and showed IC50 value of 39.70 nM against human AChE.
Molecular modeling studies indicated that the two methoxyl groups
at 6- and 7-positions of compound 13 played an indispensable role
in exerting biological activity [30]. Therefore, compound 13 could
be considered as a highly active and selective AChE inhibitor with
elevated therapeutic potentiality in the treatment of AD.
The deposition of A
in the brain is hypothesized to be the
main cause of neuronal cell death in AD patients, thus the preven-
tion of the aggregation of A
represents an alternative therapeutic
strategy that directly targets AD pathogenesis [31,32]. Many small
molecules have the ability to interfere with the process of A
ag-
gregation [33] and functionalization of small aromatic molecules
could be served as the rational design of A
aggregation inhibitors.
Tetrazole functionalized coumarin 14 showed a significant increase
in reducing the equilibrium plateau, which demonstrated the poten-
tiality of tetrazole functionalized derivatives as inhibitors of A

aggregation to treat AD [34]. Comparative study showed that the
enhanced inhibitory ability might result from the presence of ben-
zothiazole and tetrazole structures, which was capable of disrupting
multiple sites of AD aggregate growth.
It was reported that the inhibitors of
-secretase (BACE1) had
great potentiality to be developed as anti-dementia drugs. Accord-
ingly, BACE1 is recognized as a valuable target for the rational
treatment of AD. Natural product 15 was identified to be a potent
mixed-type BACE1 inhibitor with IC50 value of 9.90 μM [35]. This
finding encourages lots of researchers to investigate naturally oc-
curring compounds for the cure of neurodegenerative diseases.
Butyrylcholinesterase (BChE) seems to have some effects on
the treatment of AD because it controls the level of extracellular
acetylcholine in the AD patient’s brain. Natural coumarin 16, which
CH3
CH3 H3CO O O N
4 CH3
O H3CO O O
13 OH
Coumarin Compounds in Medicinal Chemistry
N N
HN N
S O
CH3 N
N O O O
14 OCH3
CH3
was isolated from the roots of Angelica archangelica L. through
TLC bioautography guided fractionation, exhibited significant
BChE inhibitive activity with IC50 value of 7.50 μM. Structure-
activity relationship revealed that only C-8 substituted 5-
hydroxylfuranocoumarins were active [36]. This discovery provides
important structural information for specific BChE inhibitors.
Coumarin AP2243 (17) is a dual binding site AChE inhibitor,
which is able to simultaneously contact with both the central and
the peripheral anionic sites of AChE with IC50 value of 18.30 nM.
AP2243 analog 18 was obtained by the structural modification in its
side chain. Compound 18 displayed a fairly good activity (IC50 =
0.32 μM) with 10-fold less potent than AP2243 and an excellent
activity towards BACE1 with IC50 value of 0.11 μM [37]. Docking
calculation revealed that the protonated nitrogen atom could reach
the acid environment formed by the catalytic diad Asp32 and
Asp228, and the N-benzylethyl moiety was suitable for simultane-
ously fitting the S1 and S10 pockets.


Fatty acid amide hydrolase (FAAH) is an integral membrane
enzyme that catalyzes the hydrolysis of several endogenous lipid
messengers. Its inhibitors can regulate the endocannabinoid signals
and improve neuronal transmission, thus may be applied to treat
AD. Coumarin 19 displayed IC50 values of 0.28 and 2.26 μM
against rat brain FAAH and human recombinant FAAH, respec-
tively. Notably, it exerted impressive activities towards AChE and
BChE with IC50 values of 74.90 and 1.57 nM, respectively, which
were 21- and 192-fold more active than reference drug rivastigmine
[38]. It may be concluded that compound 19 might be a valuable
multitarget-directed drug candidate in AD treatment.
It has been seen that much attention has been paid on the search
for potential AChE inhibitors for the treatment of AD in recent
years. However, the action targets associated with AD are diverse.
Therefore, the development of bis- or multitarget-directed inhibitors
might still be an important trend for succedent anti-AD researches
[39,40].
3.2. Coumarin Compounds as Medicinal Agents for Anti-
Parkinson’s Disease
PD is also called paralysis agitans, it is a chronic and progres-
sive neurodegenerative disease in most of the elderly. Its main
clinical symptoms are bradykinesia, rigidity and resting tremor, and
usually accompanying with dysfunction of consciousness, recogni-
tion and memory. Monoamine oxidase (MAO) inhibitor is one of
CH3
HN
H3C N O
OCH3
O O OCH3
17 O O
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3887
OH
CH3
O O O
H3C CH3 O
O CH3
O O H3C
O
15 HO
CH3 16
CH3
currently effective drugs for the retard to PD [41]. MAO is a flavin-
containing enzyme bound to the mitochondrial outer membrane of
neuronal, glial, and other cells, which is responsible for the oxida-
tive deamination of endogenous monoamine neurotransmitters,
trace amines, and a number of amine xenobiotics. This enzyme
exists in two distinct enzymatic isoforms, namely MAO-A and
MAO-B encoded by different genes and distributed in diverse tis-
sues [42]. Only selective MAO-B inhibitors have been utilized to
treat PD and a number of important breakthroughs have been ob-
tained in the therapy of PD [43].
Hybrids 20a-c with coumarin and resveratrol were found to be
highly selective inhibitors against MAO-B isoenzyme (Table 1).
Amongst, compound 20a bearing two methoxyl groups showed
IC50 value of 8.98 nM, SI value of > 11136, which was two times
more active and several times more selective than standard R-(-)-
deprenyl drug [44]. The IC50 value of compound 20b with m-
methoxyl moiety was 0.80 nM, which was about 24 times more
active (SI > 124595) than R-(-)-deprenyl drug (SI > 3431) [45].
Methyl substituted coumarin 20c with IC50 value of 0.31 nM, SI
value of > 300000 was 64 times more active and several times more
selective than R-(-)-deprenyl drug [46]. Contrast studies suggested
that the methoxyl group at the meta position and the methyl moiety
at para position played an important role in exerting the biological
activity and selectivity against MAO-B and all of them might be
considered as vital lead compounds for treating PD.
It is established that the introduction of halogen substituents can
affect the activity of target compounds. Coumarins 21a-b with Br
moiety at 6- or 8-position of coumarin backbone showed significant
MAO-B inhibitory activity in the low nanomolar range and with
high selectivity. Compound 21a (IC50 = 1.35 nM, SI > 74074) dis-
played superior MAO-B inhibitory efficacy to R-(-)-deprenyl drug
(IC50 = 19.60 nM, SI > 3431) [47], while compound 21b was six
times more active (IC50 = 3.20 nM) and to a great extent more se-
lective (SI > 30960) than R-(-)-deprenyl drug [48]. However, the
replacement of methoxyl group at 8-position of compound 21a by
hydroxyl moiety would decrease the activity and selectivity.
Literature has reported that some compounds with acyl or ben-
zyloxy substituted group [49] linked to C-3 or C-7 position at the
coumarin ring possessed the ability to improve inhibitory activity
and selectivity towards MAO-B. Hydrazido modified coumarin 22a
(IC50 = 3.22 nM and ratio > 31055) gave excellent inhibitory activ-
ity and selectivity towards MAO-B in comparison to reference R-(-
H
O N
5
O
HN
F
N O O O
F
O 18 CH3 19
3888 Current Pharmaceutical Design, 2013, Vol. 19, No. 21 Peng et al.

Table 1. Inhibitory Activities of Coumarins 20a-c against MAO-B Isoenzyme

R1
R2

H3C
R3

O 20
O

Substituents Biological Activities

Compounds Necessary Substituents
1 2 3
R R R IC50 (nM) SI

20a OCH3 H OCH3 8.98 > 11136 OCH3

20b H H OCH3 0.80 > 124595 OCH3

20c H CH3 H 0.31 > 300000 CH3

OCH3 O

R1 NH
R
O O O O
21a: R1 = Br, R2 = OCH3 22a: R = NH2
R2 22b: R = 4-SO2CH3-Ph
21b: R1 = CH3, R2 = Br

)-deprenyl drug. It was found that compound 22a could form two
hydrogen bonds with Tyr435 and Tyr398 of MAO-B [50].
Methanesulfonyl derivative 22b exhibited remarkable MAO-B
inhibitory efficacy with IC50 value of 1.40 nM, SI value of > 6664
[51]. It is obvious that both compounds 22a and 22b have large
potentiality to be developed as effective drugs against PD.
Different substitutions of coumarin nucleus at 3-position result
in different activity and selectivity towards MAO-B [45] specially
those with heterocyclic rings at 3-position possess higher potency
and selectivity. Compound 23 with an indole ring at C-3 position
exhibited good anti-MAO-B activity with IC50 value of 45.95 nM.
The introduction of methoxyl moiety on C-7 position increased the
ability about 50-fold. Docking studies manifested that compound 23
could form hydrogen bonds between the indole NH and target site,
and exerted
-
interactions as well as strong van der Waals forces
with Gln206, Tyr326, Leu171 and Cys172, which achieved its good
inhibitory efficacy [52]. However, compound 23 showed a weak
MAO-A inhibitory activity, which led to a small decrease in the
selectivity of MAO-B.
Literature provided evidence that coumarin 24 was a potent
(IC50 = 0.01 μM) and selective (SI > 457) MAO-B inhibitor both in
vitro and in vivo [49]. Moreover, this compound had many desir-
able properties such as rapid blood-brain barrier penetration, short-
acting and reversible inhibitory activity, slight inhibition of selected
cytochrome P450s, and low in vitro toxicity and so on. On the basis
of these observations, compound 24 may be considered as a promis-
ing clinical candidate for the treatment of PD. Molecular modeling
analysis revealed that compound 24 adopted a convergent binding
mode and the lactonic carbonyl moiety formed a hydrogen bond
with the hydroxyl group of Tyr398.

Early literature reported that electron delocalization and po-
larizability as well as hydrophobicity were crucial physical factors
for MAO inhibitors. The fused coumarin 25 with large conjugated
system demonstrated better MAO-B inhibitory activity (IC50 = 1.50
nM) than R-(-)-deprenyl drug (IC50 = 19.60 nM), and the selectivity
of compound 25 towards MAO-B was 1600-fold higher than MAO-
A isoform [53]. Therefore, the fused coumarins are also worthy to
be further investigated as potential MAO-B inhibitors.
4. ANTICANCER COMPOUNDS
Cancer is one of the most formidable threats to human health
[54], which is characterized by the arrest of cell differentiation, the
inhibition of apoptosis and the accelerated proliferation of clonal
cells. Cancer-caused mortality accounts for the overwhelming ma-
jority among various diseases and has been rising dramatically.
Since the discovery of chlormethine for the treatment of malignant
lymphoma, a variety of clinical drugs such as alkylating agents [55-
57], platinum complexes [58,59], porphyrin drugs [60], azole
agents [61-63] and so on have been well developed. However, most
of clinical drugs are poor curative effect, high toxicity, low selectiv-
ity and severe drug resistance. It is still an emergent mission to
exploit novel anticancer drugs. Coumarin compounds as potential

H H
N Cl N
H3C
Br
O O
H3CO O O 23 24 O O O CH3 25
Coumarin Compounds in Medicinal Chemistry
anticancer agents have become a rapidly developing, extremely
active and attractive topic.
4.1. Coumarin Compounds as Anticancer Agents Against
Breast Carcinoma
Breast cancer is a leading carcinoma in women of all ages and it
is often estrogen-dependent [64]. Phase I clinical trial candidate
667coumate (26), as the first coumarin-based sulphatase inhibitor to
treat hormone-dependent breast cancer in postmenopausal women,
was reported by early researches. Some recent works have also
demonstrated that coumarin compounds are potential anti-breast
cancer agents because they can form coumarin-estrogen conjugates
and selectively modulate estrogen receptor. In addition, with the
discovery of antitumor activity of novobiocin, a well-established
antibiotic agent, the investigations of coumarins as anti-breast can-
cer candidates have attracted more and more attention, and many
potent coumarin-based anticancer agents against breast carcinoma
[65-67] have been developed.
O NH2
S = 51 nM). The F atom at the p- and m-positions on the phenyl
O O O O
26
Mammea-type coumarins are a large family of isoprenylated
5,7-dihydroxy coumarin metabolites from Mammea americana L.
and other species of Mammea, Mesua as well as Calophyllum,
which exhibit a wide array of biological activities. Mammea E/BB
27 was not only able to inhibit both hypoxia-induced and iron
chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in
human breast tumor T47D cells with IC50 values of 0.96 and 0.89
μM, respectively, but also suppress the migration of MDA-MB-231
breast tumor cell at 5 and 20 μM [68]. Mechanistic studies mani-
fested that compound 27 seemed to act as an anionic protonophore
to achieve an assemblage of cellular effects, thereby uncoupling
mitochondrial electron transport and disrupting mitochondrial sig-
nal in tumor cell lines.
Heat shock protein 90 (Hsp90) has been viewed as an exciting
target in cancer drug discovery. Coumarin 28a had high potency to
induce the proteasome-mediated degradation of several known
Hsp90 client proteins and strong antiproliferative activity in MCF-7
breast carcinoma cells [69]. Taken 28a as a lead compound, deriva-
tive 28b was synthesized and exhibited superior inhibitory potency
(IC50 = 35 μM) against MCF-7 to 28a (IC50 = 45 μM). Interest-
H3COCO
CH3 OH CH3 H C
3
H3C
HO O O
R2
H3CH2C(H3C)HC O 27
R2
29a: R1 =
R3
O
R 1O O O 29b: R1 =
HO
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3889
ingly, structure-activity relationship showed that the removal of C-7
or C-8 substituent was not detrimental for hsp90 inhibitory activity
[70]. These results suggested that both compounds 28a and 28b are
deserved to be investigated in-depth.
KU-398 is a lead molecule with promising anticancer ability
through inhibiting the activity of Hsp90. Benzothiophene modified
derivative 29a at C-3 position along with the removal of 8-methyl
group exhibited lead-like activity with IC50 values of 0.98 and 0.81
μM, respectively, towards breast cancer cell lines SKBr-3 and
MCF-7, and showed binding activity to the Hsp90 C-terminus [71].
Glycosyl coumarin 29b demonstrated excellent inhibitory activity
(Ki = 9.20 nM) against carbonic anhydrase IX (CA IX) in vitro, and
a very good selectivity in inhibiting the tumor-associated CA iso-
forms [72]. Since CA IX is selectively expressed in hypoxic tumors
[73] and its presence is an independent poor prognostic marker for
breast cancer [74-76], compound 29b may be applied in combina-
tion with conventional chemotherapy or radiation to treat this carci-
noma.
Aromatase (AR) is considered as a direct target in the treatment
of breast cancer because in malignant tissues the activity of AR is
higher than that in healthy tissues. Coumarin 30 containing F atom
was identified as potent AR inhibitor, which showed an inhibitory
potency (IC50 = 47 nM) equal or slightly better than its parent (IC50
group played an essential role for the excellent activity of com-
pound 30 and this might be a safe and suitable lead molecule as
anti-breast cancer drug for further development [77].
Human 17
-hydroxysteroid dehydrogenase (17
-HSD) type 1
can regulate the biological potency of steroid hormones. The over-
expression of 17
-HSD type 1 in estrogen-responsive tissues is
related to the development of breast cancer. Thus one of methods to
discover novel drugs for breast carcinoma is to inhibit the activity
of 17
-HSD. Compound 31 was found to be a reversible and com-
petitive inhibitor of 17
-HSD type 1 with a Ki value of 53 nM [78].
It was notable that coumarin 31 could not only decrease the efficacy
of endogenous 17
-HSD type 1 in human T-47D breast cancer
cells, but also reduce the growth of estrone-dependent T-47D cells
after 48 h of incubation.
Thiophene compounds have attracted a great deal of interest in
recent years [79,80] due to their high reactivity, stability, electronic
properties and bioactivities. Thiophene-incorporated coumarin 32
exhibited good activity against breast carcinoma cell line MCF-7
with GI50 (50% growth inhibition) value of 10.80 μM [81]. It is
worthy to further study this compound for exploitation of effective
anti-breast cancer agents.
Osthole is a well-known structurally simple natural coumarin, it
is an important component of medicinal plants and herbs [82], and
O
S O R3 28a: R1 = CH3, R2 = OH, R3 = O
O CH3
O
NH CH3
O
28b: R1 = H, R2 = H, R3 = CH3
O O
R1 CH3
N S
N N
CH3, R2 = H, R3 = F
OH F
OH, R2 = CH , R3 = H
3
OH O O O
30
3890 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
O OCF3
CH3
O O
31
HO
exhibits many pharmacological activities [83]. Further modification
of osthole at C-8 and C-3 positions of coumarin skeleton with
isoamyl and 4-trifluromethoxylphenyl groups produced its analog
33. This compound possessed potent activities against MCF-7 and
MDA-MB-231 breast cancer cell lines with IC50 values of 0.24 and
0.31 μM, respectively. Its bioactivity was improved more than 100-
fold in comparison with that of osthole. Importantly, compound 33
had no growth inhibitory effect in HEK-293 normal cells [84].
Coumarin compounds 34a-b were synthesized and evaluated
for their antiproliferative activity against two breast cancer cell
lines. In case of 34a, the IC50 values against SKBr-3 and MCF-7
were 0.46 and 1.18 μM, respectively [85]. As respect to 34b, the
IC50 values towards SKBr-3 and MCF-7 were 0.11 and 0.52 μM,
respectively, which were slightly lower than 34a [86]. The low IC50
values of compounds 34a and 34b warrant further investigation as
new drugs.
Neo-tanshinlactone was reported to have significant inhibitory
efficacies against two estrogen receptor positive human breast can-
cer cell lines and to be 10-fold more potent and 20-fold more selec-
tive than tamoxifen, a selective estrogen receptor modulator used
thoroughly in breast cancer therapy [87]. Benzocoumarins 35a-c
were derived from neo-tanshinlactone, they inhibited the prolifera-
tion of MCF-7 with IC50 values of 3.80, 7.90 and 6.50 μM, respec-
tively, which were superior to tamoxifen (IC50 = 11.80 μM).
Moreover, they were capable of inducing nuclear fragmentation,
cell cycle arrest (different phases) and caspase dependent apoptosis
in MCF-7 without cytotoxic effects against normal osteoblast cells
[88].
Pyranocoumarin derivative 36 also possessed significant anti-
proliferative activity against MCF-7 cell lines with IC50 value of
3.30 μM. Removal of the phenylmethanesulfonamide moiety at C-7
position of pyranocoumarin ring resulted in the decrease of activity,
which manifested the importance of phenylmethanesulfonamide
moiety for the anti-MCF-7 potency [89].
H
R1 N R3
34a: R1 = H, R2 = (CH2)3N(CH3)2, R3 =
O
R2O O O
CH3 34b: R1 = OCH3, R2 =
CH3
O
R O
HN O
35a: R = CH3
35b: R = (CH2)2CH3
35c: R = (CH2)3CH3
Peng et al.
O S
N
H H3CO O O
CN 33
O O 32
(CH2)2CH(CH3)2
4.2. Coumarin Compounds as Anticancer Agents Against Leu-
kemia
Leukemia is a kind of progressive malignant disease with the
abnormal proliferation of hematopoietic stem cell because of their
destitute ability of further differentiation and stagnation in different
stages of cell development, which in turn inhibit normal hema-
topoiesis. Anemia, hemorrhage, infection, and organ infiltration are
the mainly clinical symptoms. Leukemia is one of the most com-
mon malignant tumors in children and youth, and can be classified
into chronic and acute ones. Recently, leukemia has been found to
be strongly refractory to chemotherapy. The results support the
necessity and importance to investigate alternative chemotherapeu-
tic strategies for the treatment of leukemia.

-Methylene--lactone moiety is a well-known important struc-
tural fragment in the cytotoxic activity of sesquiterpene lactones.
Natural coumarin 37 with
-methylene--lactone group was iso-
lated from Murraya siamensis and showed significant cytotoxicity
against HL-60 leukemia cells in a time-dependent manner. Further
studies indicated that the antileukemia activity of this compound
was attributed to its ability that induced the loss of the mitochon-
drial membrane and apoptosis by activating the activities of
caspase-9 and caspase-3 in HL-60 cells [90].
It was reported that natural organic compounds had MDR-
modulating activity and could be developed as MDR-reversal
agents [91]. Coumarin 38 from the aerial parts of Cicuta virosa L.
displayed better cytotoxicity in K562 and K562/A02 leukemia cells
with IC50 values of 0.39 and 3.09 μM, respectively than doxorubi-
cin (IC50 = 0.41 and 22.40 μM). Moreover, its efficacy to reverse
the resistance of K562/A02 cells was 7.25-fold more active than
doxorubicin [92]. The results provide a new source that contributes
to the antitumor activity of Cicuta. Additionally, sesquiterpene
coumarin 39 from Ferula gumosa exhibited an IC50 value of 8 μM
against leukemia cell lines U-937 [93].
CH2CHC(CH3)2
OCOCH3
CH3 3
N ,R =
N
H
CH3 CH3
H3C
O
O
O O O
O
S
N 36
H3C H
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3891

O O O O O O O O
O CH3
O CH3
OH
H3C
O CH3 CH2 CH3 O HO
O CH3
CH3
CH3
37 O O O CH3 38
CH3 39
CH3

OH
OH OCH3
CH3 OCH3
O
H3CO H3C CH3
H3C O
42
40 H3CO O O HO O O 41 O O O

Researches manifested that some alkaloids from Toddalia asiat-
ica, a woody liana widely distributed in Southeast Asia, South Af-
rica and tropical Africa, had antineoplastic activity [94]. Based on
this observation, natural coumarin 40 was obtained from Toddalia
asiatica. It displayed a dual effect that acted as a cell differentiating
agent and apoptosis inducer in U-937 cells, thus compound 40
might be served as a pharmacological prototype for the develop-
ment of novel antileukemic agents [95].
The combination of two or more kinds of compounds with simi-
lar biological property into one molecule is a significant strategy in
drug discovery [96]. Hydroxyphenyl coumarin hybrid 41 was pre-
pared and displayed high potency with IC50 value of 5.20 μM
against HL-60, which was about 7 times more active than resvera-
trol [97]. Further study suggested that the excellent antiproliferative
activity of compound 41 might be mediated by deregulation and
induction of apoptosis in cell cycle.
Differentiation therapy is a potential alternative method to treat
acute leukemia, which induced malignant cells into maturation
pathway. Compound 42 also had the potential to be new effective
differentiation inducers for the treatment of leukemia. It showed
high antiproliferative activity against U-937 with an IC50 value of
25.30 μM, specially inhibited the growth of U-937 cells at 72 h at
50 μM with percentage of cell inhibition of 62.5% (p < 0.05) [98].
Comparative studies revealed that the alkoxy substituent not methyl
group made the contribution for the good activity. However, cou-
marin 42 was a racemic mixture, which made it impossible to pre-
dict if both enantiomers were active or just one of them.
4.3. Coumarin Compounds as Anticancer Agents Against Lung
Cancer
Lung cancer, including small and non-small cell lung cancer, is
a typical disease in the elderly patients. With the increasing number
of smokers, the mortality of lung cancer has become an important
cause of cancer death in both men and women in developed and
developing countries [99]. For all the lung cancer patients receiving
chemotherapy, only 5% of them are able to survive more than 3
years, while for patients without treatment the survival is just 2-4
months. The high mortality results in a great requirement to develop
the improved therapeutic approaches for the treatment of lung can-
cer.
Resveratrol is a well-known natural polyphenol with multiple
biological activities [100]. The introduction of substituted resvera-
trol fragment into coumarin backbone at C-4 position produced
hybrids 43a and 43b. Compound 43a with methoxyl moiety
showed an IC50 value of 0.45 μM against H-460 lung cancer cell
lines, which was comparable to cisplatin and 28-fold more active
than resveratrol. Methyl-substituted derivative 43b exhibited more
excellent anti-H-460 efficacy (IC50 = 0.29 μM) than 43a, resvera-
trol and cisplatin respectively. Their effect was associated with a
partial cell accumulation in G2/M phase of cell cycle. Structure-
activity relationship indicated that the trans-vinylbenzene linker
was necessary for good activity [101].
Acetoxycoumarin derivatives 44a-b displayed antiproliferative
activity with LD50 (50% lethal dose) values of 89.30 and 48.10 μM,
respectively, in lung cancer cell lines A549 after 48 h treatment.
Cell cycle analysis showed that compound 44a caused cell arrest in
the S and G2 phases at 20 μM, and in the G1 phase at 40 and 60 μM,
while compound 44b induced cell cycle arrest at S/G2 phase with
increasing concentration [102].
O O
R1
CH3
R
R2 O O
H3CO O O
44a: R1 = Ph, R2 = H
43a: R = 3,5-OCH3 43b: R = 3,5-CH3 44b: R1 = CH3, R2 = N(CH2CH3)2
Heterocycles and peptidomimetics containing N-N bond have
been widely served as pharmaceutical and agricultural agents. Hy-
drazide-hydrazones using N-N linker as key structural moiety pos-
sess diverse biological properties [103-105]. Coumarin-based hy-
drazide-hydrazone 45 showed promising inhibitory effect against
non-small cell lung cancer (NCI-H460) with GI50 value of 10 μM in
comparison to doxorubicin [106].
Additionally, sulfur bridged coumarin 46 exhibited good anti-
proliferative activity (GI50 = 2.11 μM) against A549 lung cancer
cell lines in comparison with paclitaxel. Further assays demon-
strated that compound 46 could not only markedly inhibit the pro-
liferation rate of A549 cells and increase the cellular apoptosis in a
concentration-dependent manner, but also clearly induce A549 cell
cycle arrest at the G2/M phase [107]. However, the replacement of
4-methylcoumarin skeleton with isomeric 2-ethyl-4H-chromen-4-
one resulted in the dramatic decrease of activity.
O Cl CH3
N N
N N
H
CH3
O O S O O
45 46
3892 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
4.4. Coumarin Compounds as Anticancer Agents Against Cer-
vical Cancer
Cervical cancer is a disease that characterized by bowel and
bladder dysfunction, fistula, pain and bleeding. The persistent infec-
tion with sexually transmittable high-risk human papillomaviruses
is the main etiologic factor for cervical cancer. The mortality rate of
cervical cancer has dropped by almost 70% since 1979 due to the
introduction of national cervical cancer screening and human papil-
lomavirus vaccines programmes. However, the effect of vaccine is
not evident after about 20 years. Currently, cervical cancer is still a
prevalent female malignancy in many countries. Naturally, the in-
vestigations for the treatment of cervical cancer are a quite impor-
tant mission.
Fruits can be treated as an alternative source for the treatment
of cancer. Activity-guided separation of wampee [Clausena lan-
sium (Lour.) Skeels] led to natural product 47. It could significantly
inhibit (p < 0.05) the growth of human cervical carcinoma cell lines
(HeLa) with IC50 value of 0.01 μg/mL, which was more potential
than standard drug cisplatin with IC50 value of 349.90 μg/mL [108].
The action mechanism of compound 47 might be involved in dis-
turbing the cellular division during mitosis at the telophase stage or
decreasing the amount of cellular protein and mitotic index, and the
colony formation during cell proliferation. It is obvious that further
work about its anticancer activity using in vivo models is worth
investigation.
Chalcones are an important class of natural products with inter-
esting biological activities [109,110]. The combination of chalcone
with coumarin produced their hybrid 48 with a pronounced ability
against C33A cervical carcinoma cells. The IC50 value was 3.59
μM, which was slightly inferior to standard drug doxorubicin (IC50
= 0.82 μM). However, it showed around 30-fold more selectivity
towards C33A cells over normal fibroblast NIH3T3 cells [111].
Structure-activity relationship showed that the ester moiety at C-3
position was essential. It is undoubted that the results may provide
an approach to develop new potent coumarin-chalcone hybrids for
the treatment of cancer.
The application of psoralen ultraviolet A therapy in the treat-
ment of psoriasis and cutaneous T-cell lymphoma has attracted
medicinal chemists' interest in furocoumarin derivatives for devel-
opment of photochemotherapeutic drugs. Compound 49 displayed
an IC50 value of 0.40 μM against HeLa, which was 25 times lower
than reference 8-methoxypsoralen, and it showed the ability to in-
hibit cell growth in the absence of ultraviolet A irradiation. Fur-
thermore, compound 49 could intercalate into DNA between two
O O O O
OH
H3C H3C
47
CH3
OCH3
CH3 CH3
HO
CH3
H3C HO O
O O O O
50
Peng et al.
adjacent base pairs by covalent bond and exert a notable concentra-
tion-dependent inhibition of the topoisomerase II-mediated relaxa-
tion of supercoiled DNA [112].
4.5. Coumarin Compounds as Anticancer Agents Against Colon
Cancer
Colon cancer is one of the most frequent cancers in both men
and women with at least one million of new cases per year diag-
nosed worldwide. Its common treatment is surgical resection. How-
ever, nearly 40% of patients still experience disease relapse with
significant morbidity and eventual mortality. Adjuvant treatment
(e.g. chemical drugs) for colon cancer has attracted much interest in
the last few decades, which is able to not only destroy the micro-
scopic metastases, but also reduce the risk of recurrence.
Citrus is a well-known fruit with abundant bioactive organic
compounds, which may helpfully prevent lifestyle-related diseases
such as cancer. Natural coumarin 50 from the peel of Citrus fruits
was found to possess antiproliferative activity against human colon
cancer HT-29 cells with IC50 value of 47 μM [113]. This finding
provides a convenient strategy to discover novel lead compounds
for the treatment of cancer.
It is established that structural modification of novobiocin
would yield a collection of derivatives with antiproliferative ability.
Novobiocin-derived 2-indoleamide 51 was identified as a potent
inhibitor against human HCT-116 colon cancer cell lines with IC50
value of 0.17 μM. Moreover, in the presence of compound 51,
Hsp90 client proteins were induced and degraded in a concentra-
tion-dependent manner. Further researches on the location of the C-
terminal nucleotide-binding region of compound 51 and other no-
vobiocin analogs are currently underway [114].
Diallyl polysulfides are highly effective in affording protection
against cancers induced by a variety of chemical carcinogens [115].
Bis-coumarin polysulfide 52 could reduce cell viability of HCT-116
colorectal cancer cell lines in a time and concentration dependent
manner. In addition, compound 52 could induce cell cycle arrest in
the G2/M phase and finally into apoptosis by regulating the phos-
phatase activity/level of cdc25 [116]. Thus, coumarin polysulfides
are promising novel anticancer agents.
4.6. Coumarin Compounds as Anticancer Agents Against Pan-
creatic Cancer
Pancreatic cancer is a devastating disease, whose median sur-
vival is less than 6 months and the relative 5-year survival rate is
about 5.5%. Currently, there is no clinically effective therapy for
O O CH3
O H3C
N
O O CH3 CH3
O O O
CH3
49
48
NH O O
O S S
O O
NH
O O
CH3 51 H3CO 52 OCH3
Coumarin Compounds in Medicinal Chemistry
HO CH3
O OH CH3
H3C
H3C HO O O
53 CH2CHC(CH3)2 O O
complete recovery except for surgical resection. Unfortunately,
only 15-20% of patients have resectable tumor, in which only 20%
can survive up to five years after surgery. In addition, pancreatic
cancer extensively metastasizes in early stage, and it often invades
surrounding tissues aggressively. More importantly, the intrinsic
resistance of this disease to the conventional anticancer drugs in
clinical use leads to the major treatment failure. Clearly, the discov-
ery of novel effective adjunct therapies to cure pancreatic cancer is
urgently needed.
Kayea assamica is a slow growing, tall, evergreen tree and
blooms, which has been used to reduce extreme hotness in the
body. The extracts from the flower of Kayea assamica exhibited
100% preferential cytotoxicity (PC100) against human pancreatic
cancer PANC-1 cells under nutrient-deprived conditions at the con-
centration of 1 μg/mL. Natural coumarin 53 was obtained by the
further isolation of the extracts. It not only exhibited comparable
anti-PANC-1 effect with PC100 value of 1 μM to standard arctigenin
in a concentration and time dependent manner, but also induced
apoptosis-like morphological changes of PANC-1 cells within 24 h
of treatment. Structure-activity relationship manifested that the
isoprenyl moiety at C-8 position and hydroxypropyl group at C-4
position were essential for the activity since the replacement of
either of them with other substituents led to significant decrease in
efficacy [117].
Long chain isoprenyloxy modified coumarin 54 also showed
strong cytotoxicity against PANC-1 cancer cells with PC100 value of
6.25 μM within 24 h under low oxygen and nutrient-deprived con-
ditions [118]. Comparative tests revealed that the long ether chains
at 7-position played an important role in its anticancer potentiality
and the precise location of the isoprenyloxy chain was not as impor-
tant for cytotoxic activity as the length of the ether chain.
Human NAD(P)H quinone oxidoreductase-1 (NQO1) is related
to several types of tumor cells including MIA PaCa-2 pancreatic
tumor cells. The common anticoagulant dicoumarol was found to
be high sensitive to NQO1, which aroused the curiosity of many
researchers to investigate its derivatives as anticancer agents. Modi-
fication of dicoumarol at 7- and 8-position using benzo moiety
produced its derivative 55. It showed superior inhibitory efficacy
(IC50 = 0.18 nM) against NQO1 to dicoumarol (IC50 = 2.60 nM),
which might be responsible for the increased hydrophobic interac-
tions with active site residues of NQO1. However, compound 55
displayed low toxicity with IC50 value of 190 μM towards MIA
PaCa-2 pancreatic tumor cells at 24 h. This suggested that there was
no systematic relationship between cytotoxicity and NQO1 inhibi-
tory potency [119].
4.7. Coumarin Compounds as Anticancer Agents Against Gas-
tric Carcinoma
Gastric cancer is still difficult to pretest despite of a slowly
declining incidence and mortality recently. Majority of patients are
diagnosed at advanced stage when curative surgery is impossible.
Surgical resection remains the primary curative treatment modality
offering hope for the cure of gastric cancer, which is still only ap-
proximately 30% of survival for 5 year and subjects to locoregional
recurrence or distant metastasis. Interestingly, patients with pallia-
tive chemotherapy show an improvement in both quality of life and
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3893
CH3 OH OH
H3C CH3 O OO O
O 54 55
overall survival, although there is no internationally accepted stan-
dard of chemotherapy regimen for gastric cancer. These observa-
tions suggest that the use of chemotherapy may be a potential strat-
egy for the cure of gastric carcinoma and the researches to search
new therapeutic approaches are urgent and valuable.
Natural product 56 was isolated from Corydalis heterocarpa, a
biennial herb growing on sandy beaches along the western coast of
Korea and used as a folk medicine for travailing spasm. It exerted
potent antiproliferative activity against AGS human gastric cancer
cells with IC50 value of 42.70 μM and inhibited the proliferation of
the AGS cells at rate of about 54% at 100 μM [120]. Further study
indicated that the potent inhibitory effect of compound 56 might be
produced by the induction of apoptosis through activating Bax, p53
and p21 expression in a dose dependent manner.
Telomerase is usually active in the early stages of life and turns
dormant in most somatic cells during adulthood. However, it gets
reactivated and works tirelessly in cancer cells. This makes telom-
erase be an important target for the development of cancer treat-
ment, specially for gastric cancer [121]. It was reported that some
compounds with dihydropyrazole unit were used as effective te-
lomerase inhibitors. Stimulated by these, coumarin derivative 57
with 4,5-dihydropyrazole moiety was synthesized. It exhibited bet-
ter activity against human gastric cancer cell SGC-7901 with IC50
value of 2.69 μg/mL than 5-fluorouracil (IC50 = 7.38 μg/mL).
Moreover, compound 57 had superior inhibitory ability (IC50 = 2.00
μM) against telomerase to positive control ethidium bromide and
could bind well with the telomerase active site through two more
optimal intramolecular hydrogen bonds [122].
Microtubules, the polymers of
- and -tubulin heterodimers,
play an essential role in the formation of mitotic spindle and segre-
gation of chromosome in eukaryotic cell. Thus, it can be considered
as an attractive target for anticancer drugs. Compound 58 was iden-
tified as a novel microtubule inhibitor, which possessed a remark-
able antimitotic potentiality in 5-fluorouracil-resistant human gas-
tric cancer cell line SNU-620-5FU and its parental cell SNU-620 by
destabilization of microtubules and subsequent mitotic arrest [123].
4.8. Coumarin Compounds as Anticancer Agents Against other
Cancers
Apart from the above mentioned cancers, coumarin compounds
still exert influential potency against other cancers [124-126].
Mantle cell lymphoma (MCL) is an aggressive B-cell lym-
phoma with rapid relapse after an initial response or primary resis-
tance to standard chemotherapy. The mutation/overexpression of
apoptosis-related genes p53 is an adverse prognostic indicator of
MCL. Based on this, the development of novel compounds that
target p53-independent signalling pathway attracts considerable
interest in the treatment of MCL. Natural coumarin 59, derived
from the stem bark of Calophyllum brasiliense, was more promi-
nent efficacy in mt-p53-bearing MCL cells than in those with wild-
type (wt) p53 through upregulation of Noxa and BAK activation. In
addition, the combination of compound 59 with bortezomib or
doxorubicin led to the enhanced antiproliferative effects independ-
ent of p53 status [127].
Prostate cancer, accounting for 10% of all new cases of cancer,
is one of the most common causes of death from cancer in men
3894 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
COCH3
N N
O O
O
H3C O O
56 57
HO3SO CH3
H3C CH3
S
O CH3
N Br
H3CO O O
HO O O
59 60
O CH3
CH3
because of about 10% to 60% of the patients with prostate cancer
experience treatment failure. One of the treatment methods for
prostate cancer is to regulate the biosynthesis or action of androgen
on the androgen receptor. Naturally, 17-hydroxysteroid dehydro-
genase type 3 (17-HSD3), which can catalyze the final step in the
biosynthesis of androgen and is expressed at high level in some
tissue with prostate tumor, is viewed as an attractive molecular
target of a small-molecule inhibitor for the treatment of prostate
cancer. Compound 60 was found to be potential 17-HSD3 inhibi-
tor with IC50 value of 1.50 nM. Structure-activity relationship
showed that the nature of substituents at C-4 position was the main
influence, and the steric allowance, the thioether linker, the elec-
tron-donating methyl group as well as the basicity of nitrogen all
provided contribution to its strong activity [128].
Ovarian cancer is the eighth most common cause of death
caused by cancer in women and the median survival of the patients
with ovarian cancer is only 3 years. Moreover, the rise of resistance
to drugs for ovarian cancer forces researchers to develop new drugs
to treat this cancer. Nifurtimox was reported to exhibit cytotoxicity
against cells lines derived from ovarian cancer with low efficacy.
Structural modification of nifurtimox afforded its coumarin-based
derivative 61. This compound could induce the apoptosis of plati-
num-resistant ovarian cancer cell line OVCAR-3 through inhibitory
effects on oncogene ras, down-regulation of DNA-pk KU-80
subunit expression and activation of AKT. Compound 61 was much
sensitive in comparison to nifurtimox, which might result from an
additive cytotoxic effect of the synthetic lipophilic coumarin skele-
ton in conjunction with the 1-aminotetrahydrothiazane ring origi-
nally derived from nifurtimox. Except for these potencies, com-
pound 61 could delay the progression of OVCAR-3 cells in G2
phase and affect the integrity of mitochondrial [129]. Further stud-
ies on its in vivo anti-ovarian cancer activity are underway.
5. ANTIOXIDATIVE COMPOUNDS
Reactive oxygen species (ROS) are by-products of metabolic
processes in active cells of aerobic organisms. They play pivotal
roles in many physiological events such as signal transduction reac-
tion cascades. The deregulation between the formation and scav-
enging of ROS results in elevated oxidant species, which have dele-
terious effects on almost all tissues and are implicated with aging
process, neurodegeneration, multiple sclerosis, cardiovascular dis-
eases, inflammation and cancer etc. Drugs with antioxidative activ-
ity can work in several ways, for instance, as inhibitors of ROS
formation, free radical scavengers, chain breaking antioxidants, or
as transition metal chelators. The researches on active antioxidants
of natural and synthetic compounds have received great attention. A
Peng et al.
O
CH3 N
N O O
58
CH3
Cl SO2
N
N
CH3 CH3
O O
61
number of coumarins have been found to exhibit antioxidant prop-
erty [130,131] through the binding with Fe(III) ion, thereby inhibit-
ing the formation of hydroxyl radical and hydrogen peroxide pro-
duced by Fenton’s reactions [132].
5.1. Hydroxyl Coumarins as Antioxidants
Hydroxyl coumarins specially 4-hydroxycoumarins have great
effect on the formation and scavenging of ROS, and thus influence
the processes involving free radical-mediated injury. Literature
found that the antioxidative efficacy of hydroxycoumarins was
mainly responsible for the hydroxyl group [6], which was potent


H donors for free radical acceptors due to electron delocalization
across the molecule.
Amines constitute a significant class of compounds and are of
much interest in medicinal and pharmaceutical chemistry. Cou-
marin-based amine 62 with p-nitrophenyl group possessed re-
markably radical-scavenging activity with IC50 value of 25.90 μM,
which was comparable to standard BHT (butylated hydroxytolu-
ene). The effective scavenging efficacy might be responsible for the
presence of hydroxyl and amino groups, as well as the hydrogen
bonds formed between them [133]. However, compound 62 exhib-
ited a slightly inferior inhibition percentage (67.8%) of lipid per-
oxidation in a linoleic acid emulsion to reference
-tocopherol
(74.8%) at the concentration of 1000 μM.
Styryl carbonyl containing compounds were reported to have
outstanding bioactivity. Incorporation of this structural fragment
into coumarin backbone afforded derivative 63, which exhibited
good antioxidative activity with EC50 (50% effective concentration)
value of 2.10 μM. When phenyl group was replaced by naphthyl
moiety, there was no difference on antioxidative activity. However,
the replacement of p-bromo moiety by p-methoxyl group resulted in
total loss of antioxidative ability [134]. Interestingly, if the p-bromo
moiety was substituted by p-methyl group, the antioxidative effi-
cacy (IC50 = 2.07 μM) would not be affected [135].
NO2 OH O
OH CH3
N
H
O 62 O O 63 Br
O
Naturally occurring lipoic acid (LA) is present in all kinds of
prokaryotic and eukaryotic cells with reduced dithiol (DHLA) form
and oxidized disulfide form. The antioxidant activity of the LA/
DHLA redox couple has been paid a great deal of attention due to
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3895

OH O O O OH CH2CH3 S
H3C
S
R 65a: R = CH(CH3)2
N n N S 65b: R = Ph N
4 H
H H 65c: R = H
64a: n = 6, R = H R HO O O 66
O O HO O O
64b: n = 8, R = CH3

their remarkable antioxidative activity in vitro and in vivo against

many free radicals. The introduction of -lipoic acid to coumarin H
N NO2
scaffold led to derivatives 64a and 64b, which exhibited signifi- N


cantly stronger HO scavenging activity than LA [136]. Notably,
these two compounds had no toxic effects in doses up to 0.50 N O
CH3 CH3
mmol/kg body weight in acute toxicity experiments.
O N N
Some dihydroxycoumarin derivatives have been reported to
possess antioxidative activity [137,138]. 5,7-Dihydroxycoumarins
65a-c were found to be effective antioxidants by different assay O O
O O O
methods. As to DPPH (2,2-diphenyl-1-picrylhydrazyl) radical- 67 68
scavenging activity, compound 65b was the most potent one, which
suggested that the introduction of phenylacetoxyl group to cou-
marin nucleus had a positive influence on its antioxidative activity. O
O
As to the superoxide radical anion-scavenging activity, compound NO2
N
65c exhibited superior activity to 65a and 65b, suggesting that N
short-chain substituents were more active than long-chain ones. CH3
While in the H2O2/NaOH/DMSO system, compound 65a was dem- O O O 69
onstrated to be the best radical scavenger among these three com-
pounds [139]. These results showed that the introduction of 4-ethyl O
and 6-acetoxyl groups had appositive effect on the antioxidative NH2
activity. More importantly, the protective activities in living cells S
against baicalein-induced cytotoxicity seemed to be not related to


their HO -scavenging or -reducing activities. S
O O N
Literature showed that several benzothiazole derivatives dis- SH 70
played promising antioxidant property [140]. Benzothiazoline
modified coumarin 66 showed good DPPH scavenging potency Thiophene and benzothiazole derivatives were found to possess
(IC50 = 7.60 μg/mL) and almost 80% of DPPH radicals were scav- analgesic and antiinflammatory activities. The combination of
enged at the concentration of 100 μg/mL. Moreover, compound 66 coumarin and benzothiazole using substituted thiophene as a linker



exhibited more than 50% ABTS scavenging activity at the con- afforded hybrid 70, this compound demonstrated good antioxidative
centration of 15 μg/mL. Comparative tests revealed that both the N- activity with 75.64% inhibition in comparison to ascorbic acid
or O-alkylation and the alteration of benzothiazoline ring into thia- [145]. This might be attributed to the presence of both thiazole and
zolidine or benzothiazole rings diminished the activity in compari- thiophene moieties, the aromaticity and large conjugation as well as
son with compound 66 [141]. the oxidation of S–H to S–S.
5.2. Non-hydroxyl Coumarins as Antioxidants Amide linked coumarin 71 exhibited comparable in vitro anti-
Recently, a lot of non-hydroxyl coumarin compounds have also oxidant activity to standard ascorbic acid using DPPH, nitric oxide
been reported to possess antioxidative ability.
3-Pyrroline modi- and hydrogen peroxide methods. The mechanism of compound 71
fied coumarin 67 was synthesized for its antioxidative potentiality. as an antioxidant agent might depend on the benzyl hydrogen atom,
Fortunately, compound 67 manifested to be a promising antioxidant where this atom was under the influence of two effects. One was
agent and exerted excellent in vitro inhibitory profile (100%) on the resonance effect of benzyl hydrogen, which made the easy re-
lipid peroxidation at 100 μM compared to standard trolox (63%) lease of hydrogen as a free radical, while another was the inductive
[142]. Contrast tests suggested that the alteration of the position of effect on benzene ring, which made the oxygen and nitrogen atoms

3-pyrroline ring resulted in different activity. push the electrons toward a carbon free radical, resulting in the
molecule to become stable [146].
Compounds with pyrazolone ring are associated with broad
spectrum of biological activities. Coumarin-based pyrazolone 68 Coumarin-based Schiff base 72 was identified to be an effective
exhibited moderate DPPH scavenging effect. Structure-activity antioxidant using multiple assay methods [147]. In DPPH assay, it
relationship showed that the m-nitro group played an important role showed better radical scavenging activity with IC50 value of 16.21
in the antioxidative ability due to its effect of orientation [143]. In μM than standards BHT, butylated hydroxyanisole (BHA) and
view of this, further modifications of this kind of compounds are ascorbic acid, respectively. In ABTS+ radical assay, though com-
worthy to be done. pound 72 displayed lower ability than BHA, it exhibited stronger
ABTS+ radical scavenging efficacy (IC50 = 7.76 μM) than refer-
It has been reported that compounds substituted by 1,3,4-
ences BHT and ascorbic acid, which might depend on the NH or
oxadiazoles displayed a diversity of biological activities. Oxadia-
OH group in the molecule. In superoxide anion radical assay, com-
zole modified coumarin 69 exhibited comparable antioxidative
pound 72 exerted more excellent superoxide anion radical scaveng-
activity against free radicals DPPH and ABTS+ with EC50 values of
ing potency with IC50 value of 33.12 μM than BHA, which might
5.0010-3 and 0.05 mmol/L to reference trolox with EC50 values of
be responsible for the benzyloxy group at position 6 of coumarin
5.0010-3 and 0.11 mmol/L, respectively [144]. However, the trans-
structure.
formation of nitro moiety into methoxyl group decreased the activ-
ity. Lipoxygenases (LOs) are a family of iron-containing enzymes
and can catalyze the dioxygenation of polyunsaturated fatty acids
3896 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
H R1
N O
O N
O O
O 73a: R1 = H, R2 = H
O O 71
into lipids. The majority of LO inhibitors are antioxidants or free
radical scavengers. Coumarins 73a and 73b were found to be potent
LO inhibitors. Compared to the reference compound nordihy-
droguaiaretic acid, the inhibition percentage of compounds 73a-b
was 86% and 62%, respectively [148]. The detailed structure-
activity relationship studies of this kind of compounds are currently
underway.
5.3. Fused Coumarin Compounds as Antioxidants
The fused coumarin compounds include furocoumarins with a
five-membered furan ring attached to the coumarin structure, pyra-
nocoumarins similar to furocoumarins but containing a six-member
ring and other ring fused coumarin derivatives. Recently, some
fused coumarins have been investigated in the aspect of antioxida-
tive activity and several achievements have been acquired [149].
Angelica species are one of the most important genera of me-
dicinal plants that are still in use in traditional medicine as antiin-
flammatory, diuretic, stimulant agent and so on. Natural product 74
was isolated from the aerial parts of Angelica urumiensis and found
to possess moderate antioxidant activity with IC50 value of 170
μg/mL by the DPPH radical scavenging assay [150].
O OO O CH3
H3C
H3C O O CH3 O
H3C O O
H3C
CH3 O H3C
O terial agents [163-165]. Some naturally occurring coumarins such
74
The fused coumarin 75 with 1,4-thiazepine fragment showed
promising DPPH radical scavenging activity with IC50 value of 0.12
mM, which was less than the reference drug quercetin (IC50 = 7.92
μM) [151]. However, compound 75 exhibited more potent reducing
power in comparison with quercetin. Structure-activity relationship
demonstrated that the thiazepine and 4-methoxyphenolic groups
were essential for the antioxidant activity.
CH3
HN S OH HO
O O O the coding for resistance to a single drug or a specific resistance
O O
76
75 OCH3 Cl
In addition, p-chlorophenyl modified furocoumarin 76 was
found to be an appreciable antioxidant with an IC50 value of 440
μg/mL against free radicals in comparison to the standard drugs
Peng et al.
OCH3
CH3
HO
N R2
O O
O
72 73b: R1 = Br, R2 = OCH3
O O O
ascorbic acid and 5-fluorouracil respectively [152]. Benzocoumarin
77 gave high LO inhibitory activity with IC50 value of 100 μM,
showing a promising antioxidant profile [153]. Further study indi-
cated that the inhibitory activity of compound 77 might be related
to the presence of the free hydroxyl group, which might be able to
reduce the iron species in the active site to the catalytically inactive
ferrous form.
6. ANTIBACTERIAL COMPOUNDS
Bacterial infection is a kind of common and frequently occur-
ring infective diseases all around the world, particularly in Indian
subcontinent, portions of South America and tropical fraction of
Africa. The morbidity and mortality because of food poisoning,
rheumatic, salmonellosis and diarrhea from bacterial infection are
the major health problems [154,155]. Though a large number of
antibiotics and chemotherapeutics are available for clinical use, the
treatment of bacterial infectious diseases still remains an important
and challenging problem [156,157] due to a series of factors such as
emerging infectious diseases, severely adverse effects, narrow anti-
bacterial spectrum as well as single dosage form. More importantly,
the increasing number of multidrug resistant microbial pathogens
[158,159] like methicillin-resistant Staphylococcus aureus
(MRSA), Staphylococcus epidermidis (MRSE), vancomycin-
resistant Enterococccus faecium (VRE) and carbapenems-resistant
Enterobacteriaceae (e.g. NDM-1) as well as some Mycobacte-
rium tuberculosis forces a real need to develop new compounds
with distinct mechanisms from the well-known classes of antibacte-
rial agents [160,161]. 1,2-Benzopyrone containing coumarin com-
pounds, structurally similar to clinical antiinfective quinolone drugs
with benzopyridone backbone [162], which inhibit ATPase activity
of bacterial DNA gyrase by competing with ATP for binding to the
B subunit of the enzyme, have been considered as potential antibac-
as novobiocin (78a), chlorobiocin (78b) and coumermycin A1 (79)
have been found to be an unprecedented class of antibiotics, spe-
cifically against Gram-positive bacteria [7,8]. Though antibacterial
coumarins have currently poor water solubility, toxicity in eukaryo-
tes and low activity against Gram-negative bacteria, they have
drawn renewed attention because of their prominent antibacterial
properties against MRSA and MRSE [166].
6.1. Natural Coumarin Compounds as Antibacterial Agents
Natural products are one of the most reliable and successful
source of drug leads [167] with less toxic and side effects in com-
parison to synthetic ones. In recent years, the multidrug resistance
(MDR) of bacteria associated with the expression of mutated genes,
mechanism and the modulation of multidrug efflux pump or porin
O O
expression involved in transport [168,169] has become an aggravat-
77 ing problem. Interestingly, several natural compounds have been
found to be able to inhibit bacterial efflux pumps and combat resis-
tant bacteria [170,171]. This discovery encourages workers to in-
vestigate naturally occurring coumarin compounds isolated from
plants, animals and microorganisms as new-generation antiinfective
agents against many kinds of bacterial strains.
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3897

CH3 H3C CH OH
3 H
OH O N O
OH O O
H3C CH3 H
H N CH3
O N H3C
H3C O O O O O

O H3C OH CH3 N
O O O O CH3 H3C CH OH H O
3
OH R1 CH3 O NH
O R2 O O
H
H3C N
78a: R1 = CH3, R2 = NH2 Novobiocin O O O O
78b: R1 = Cl, R2 = 2-(5-CH3-pyrrolyl) Chlorobiocin
OH CH3
79 Coumermycin A1

Natural compound 80 with plumbagin as pharmacophoric moi-

ety showed significantly enhanced efficacy against multidrug resis-
tant bacteria of Enterobacteriaceae (AcrAB-TolC) and Pseudo-
monas aeruginosa (MexAB-OprM) in the presence of the efflux
pump inhibitor, specially its MIC (minimum inhibitory concentra-
tion) value against Escherichia coli (AG100A) was up to 32 μg/mL
[172]. The results demonstrated that AcrAB-TolC and MexAB-
OprM efflux pumps were involved in the resistance of Gram-
negative bacteria to natural products.
Previous work reported that the extract of pigeon pea leaves
showed antioxidant activity [173]. Recently, it has been found that
cajanuslactone 81, a new natural coumarin from pigeon pea leaves,
possessed good activity in vitro against Staphylococcus aureus
(ATCC 6538). The MIC and MBC (minimum bactericidal concen-
tration) values of compound 81 were 0.03 and 0.12 mg/mL, respec-
tively, and the bacteria were killed completely after exposure with
coumarin 81 for 4 h. Further study revealed that the prenyl substi-
tuted derivative at 8-position and the presence of hydroxyl moiety
at 7-position played an important role in exerting antibacterial ac-
tivity and its mode of action towards Staphylococcus aureus was
associated with the loss of membrane integrity [174].
CH3 O OH OCH3
CH3
O O O HO O O
H3C
81
80
HO CH3
H3C CH3
Several Ferulago species, used since ancient times in folk
medicines for their sedative, tonic, digestive and aphrodisiac prop-
erties, have been a source of biologically active coumarins. The
extraction from Ferulago campestris, an annual or perennial herb
with small flowers that grows in the Mediterranean area, led to the
isolation of aegelinol 82a and agasyllin 82b. In contrast with cefo-
taxime, tetracycline and benzyl penicillin sodium, both of them
were effective against Staphylococcus aureus, Salmonella thypii,
Enterobacter cloacae and Enterobacter earogenes with MIC values
of 16 and 32 μg/mL, respectively. In particular, compounds 82a
and 82b showed a dose-dependent anti-Helicobacter pylori activity
with MIC values between 5 and 25 μg/mL [175].
Ethulia conyzoides, an Egyptian plant that belongs to Composi-
tae family, has been employed in folk medicine as antihelminthic
agent for round worms and abdominal disorder. Coumarins 83a and
83b were isolated from the aerial parts of Ethulia conyzoides and
RO
H3C
O O O
H3C
H3C
82a: R = H
82b: R = CH3
O
O
HO CH3
R1
O CH3
R2 83a: R1 = OH, R2 = HC CH2
CH3 O
83b: R1 = H, R2 =
O O
exhibited high activity against Gram-negative and Gram-positive
bacterial strains in comparison with ampicillin and amoxicillin
[176].
The deciduous large-sized tree Aegle marmelos is a medicinal
plant found in India, Thailand, and several southeastern Asian
countries, which shows various bioactivities [177,178]. Xan-
thoarnol 84 from the green fruits of Aegle marmelos gave a compa-
rable antibacterial activity against Enterococcus faecalis to vanco-
mycin. The MIC value of compound 84 was 18.75 μg/mL, which
could be viewed as a potential antibacterial agent [179]. Addition-
ally, the isolated constituent ulopterol 85 [180] from Toddalia asi-
atica (L.) Lam., a widely used plant as a folk medicine in India
[181,182], showed superior antibacterial activity against Staphylo-
coccus epidermidis (MIC = 15.62 μg/mL) to streptomycin (MIC =
25 μg/mL).
Insects have been considered as an important source of antimi-
crobial peptides. However, the studies on similar small non-peptide
molecules with antibacterial activity from insects are still in an
infancy stage. The secondary metabolite 86 from red ants displayed
moderate antibacterial efficacy (MIC = 25 μg/mL) against Bacillus
subtilis, which suggested that the researches on ants' metabolites
could be served as another approach to discover antibacterial com-
pounds [183].
Actinomycetes are a promising resource for new lead com-
pounds in drug development since many secondary metabolites
such as erythromycin, streptomycin and tetracycline with unusual
structures and biological activity have been extensively used in
clinic. Coumabiocin B (87) exhibited good inhibitory activity
against Streptomyces 85E [184]. Structure-activity relationship
revealed that the amino and L-noviose moieties as well as the sub-
stituents attached to these fragments had a significant impact on the
antibacterial activity.
3898 Current Pharmaceutical Design, 2013, Vol. 19, No. 21 Peng et al.

O
HO
H3C O F COOH

HO N
H3C O N N
O O
84 O O 88

CH3
HO CH3 O O
R
H3C
N N
OH
H3CO O O HN
O O 89a: R = 6-Br
85 S 89b: R = 7-OH

HO A lot of literature has reported that the thiazolyl incorporated

H3C
HO
H3C O O O against Haemphilus in
uenzae and Mycobacterium tuberculosis
CH3 86
O interpreted by the introduction of bromine atom and hydroxyl
O CH3
O NH2 OH
H
H3CO OH N bulky imine substituents could result in the decrease of activity as a
CH3
H3C O Helicobacter pylori, the spiral-shaped Gram-negative bacteria
O O O O 87
H3C
CH3
Clearly, naturally occurring coumarins isolated from a diversity
of plants, animals and microorganisms have great potentiality as
antibacterial agents against various Gram-positive and Gram-nega-
tive bacteria, specially towards multidrug resistant ones. The results
provide an original and green strategy for scientists to develop anti-
bacterial coumarin compounds with good therapeutic effects.
6.2. Synthetic Coumarin Compounds as Antibacterial Agents
Up to date, a lot of naturally antibacterial coumarin compounds
have been extracted and purified. However, the application of
active coumarins separated from natural resource is very rare for
that the limited quantity and quality can not meet human's needs.
For this reason, numerous researchers devoted to the synthetic
antibacterial coumarin compounds [185-188]. According to the
molecular structure, the antibacterial coumarins could be divided
into monosubstituted, disubstituted and polysubstituted ones.
6.2.1. Monosubstituted Coumarins as Antibacterial Agents
Monosubstituted coumarin compounds are defined as those
with only one substituent on coumarin skeleton. In recent investiga-
tions on synthetic antibacterial coumarin derivatives, substitution at
3- or 7-position of coumarin backbone is the common strategy for
most of monosubstituted coumarins [189,190].
Quinolones are well-known antibacterial drugs with broad an-
timicrobial spectrum. Combination of ciprofloxacin and coumarin
ring yielded their hybrid 88 with potent in vitro antibacterial activ-
ity against Gram-positive and Gram-negative organisms (MIC =
0.01-0.39 μg/mL) in comparison to reference drugs norfloxacin,
ciprofloxacin and enoxacin (MIC = 0.01-1.56 μg/mL). However,
the alteration of carbonyl moiety to an unsubstituted or substituted
oxime group could not significantly improve the activity against
most of tested strains. Therefore, further investigations of com-
pound 88 should focus on the modification of the substituents at
different positions of coumarin ring to improve the biological activ-
ity [191].
coumarins possessed significant biological activity [192-194]. Hy-
drazinyl thiazolyl bis-coumarins 89a-b displayed remarkable anti-
bacterial activity. Interestingly, compound 89a was highly active
H37Rv with MIC values of 15 μM. While compound 89b showed
more excellent inhibitory efficacy against Staphylococcus aureus
(MIC = 17 μM) than tetracycline (MIC = 70 μM). These might be
group. The replacement of coumarin ring by a modified benzene
ring would achieve similar activity. However, the presence of two
consequence of steric clash [195].
with polar flagella, lives near the surface of human gastric mucosa,
which has unique mechanism to avoid the bactericidal acid envi-
ronment in the gastric lumen. Thus, Helicobacter pylori infection is
the most known risk factor for the occurrence of gastric diseases,
and is difficult to cure. Fortunately, some conjugated coumarin-
thiazole compounds were reported to exhibit anti-Helicobacter
pylori activity. Coumarin-thiazole derivatives 90a-c, bearing furan,
pyridine and naphthalene ring on the hydrazone nitrogen atom,
demonstrated good efficacies (MIC = 8 μg/mL) against some clini-
cal Helicobacter pylori strains in comparison with the reference
drug metronidazole (Table 2) [196].
Thiazolidine-4-one ring is an important fragment in many syn-
thetic drugs, its derivatives display broad bioactive spectrum.
Therefore, thiazolidine-4-one was introduced into coumarin skele-
ton by oxazole linker to produce hybrids 91a and 91b, both were
more active against the tested bacteria with MIC values ranging
from 8 to 22 μg/mL than standard drug streptomycin (MICs = 15-
20 μg/mL) [197]. Additionally, compounds 92a-b, analogs of 91a-
b, also showed superior antibacterial activity (MICs = 7-20 μg/mL)
to standard drugs streptomycin and penicillin with MIC values be-
tween 10 and 20 μg/mL [198]. The obtained results revealed that
the 2,6-difluorophenyl groups in 91a, 92a and 1,3-benzodioxol-5-yl
moieties in 91b, 92b might play important contribution to the sig-
nificant inhibitory activity.
Researches showed that many N'-acylhydrazones exhibited
promising anti-Mycobacterium tuberculosis activity comparable to
the first-line anti-tuberculosis (TB) drugs such as isoniazid, rifam-
picin and pyrazinamide [199-201]. Inspired by this observation,
coumarin 93 with N'-acylhydrazone group was designed and syn-
thesized to screen for its anti-Mycobacterium tuberculosis activity.
Compound 93 displayed a significant activity against Mycobacte-
rium tuberculosis ATCC 27294 with MIC value of 50 μg/mL,
while the MIC value of the first-line drug pyrazinamide was > 100
μg/mL. In addition, its antitubercular activity was subjected to the
cellular viability in non-infected or Mycobacterium bovis Bacillus
Calmette-Guerin (BCG)-infected macrophages [202]. The results
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3899

Table 2. Inhibitory Activities of Coumarins 90a-c against Bacterial Strain

HN N
N R2
S R1

90
O O

Substituents Activity
Compounds Bacterial Strain Necessary Substituents
R1 R2 MIC (μg /mL)

90a H fur-2-yl 8 fur-2-yl

90b CH3 pyridin-3-yl Helicobacter pylori 8 pyridin-3-yl

90c H naphtalen-1-yl 8 naphtalen-1-yl

substituted derivative 95 was found to be 2- to 8-fold more potent

N O
than ciprofloxacin, the 8-OCH3 ciprofloxacin, moxifloxacin and
N rifampin, and comparable to gatifloxacin against Mycobacterium
O tuberculosis H37RvATCC 27294 [207]. However, its lipophilic
O O S character was moderate (logP = 2.11), which demonstrated that the
R
lipophilicity was not the sole parameter affecting the antimycobac-
91a: R = 2,6-FPh terial activity.
91b: R = 1,3-benzodioxol-5-yl
O
N O
O F COOH
R
O N
N
S N N
O O HN
H3CO O O 95 OCH3
92a: R = 2,6-FPh
92b: R = 1,3-benzodioxol-5-yl

may be a good starting point for the discovery of new lead com-
pounds to treat multidrug-resistant TB.
Fatty acids (FA) are known for their antimicrobial activity.
However, FA-ester analogs have received less attention despite of
the fact that such molecules have been found to be associated with
diverse biological activities. FA-ester 94 showed equivalent anti-
bacterial activity against Streptococcus pyogene, Staphylococcus
aureus and Escherichia coli species with MICs of 32 μg/mL to
standard drug chloromycetin. Comparative study revealed that the
hydroxyl group in the alkenyl side chain was essential for its good
antibacterial efficacy [203].
O considerably active against many bacterial strains at the concentra-
NH
N
O O OH
93
O
O O
6
CH3 OH
3
94
6.2.2. Disubstituted Coumarins as Antibacterial Agents
Some literature found that a number of disubstituted coumarin
derivatives possessed antibacterial activity [204-206]. As above
mentioned coumarin-ciprofloxacin hybrid 88, compound 95 was
obtained by further modification on the coumarin ring. Methoxyl-
O OCH3
Cl
N
O O 96
Cl O
Azetidinone is an exciting pharmaceutical fragment in drug
discovery. The strong activity of the famous antibiotics such as
penicillins, cephalosporins, thienamycins, nocardicins, aztreonams
as well as carbapenems is attributed to the presence of the 2-
azetidinone ring. 2-Azetidinone incorporated compound 96 was
tion of 25 μg/mL, specially against Escherichia coli and Shigella
dysentery with MICs of 1 μg/mL [208]. Structure-activity relation-
ship showed that the introduction of chlorine substituent in the
coumarin ring elevated the antibacterial potency.
Bis-coumarin 97 was prepared in order to develop new more
active antibacterial coumarins. It exhibited potential activity against
all the tested bacterial strains with MICs between 12.50 and 25
μg/mL. For the anti-Klebsiella pneumoniae potency, compound 97
gave equivalent MIC and MBC values to standard ciprofloxacin
O
(MIC = 12.50 μg/mL, MBC = 50 μg/mL). Thus, compound 97 may
be a lead molecule to develop potent antibacterial agent [209].
Thiazoles specially 2-amino ones were reported to have re-
markable antibacterial ability. 2-Aminothiazolyl modified coumarin
98 displayed comparable antibacterial activity (MIC = 31.25
μg/mL) against Staphylococcus aureus and excellent efficacy to-
wards Escherichia coli (MIC = 62.50 μg/mL) in contrast with strep-
tomycin. The good activity was also responsible for the two hydro-
3900 Current Pharmaceutical Design, 2013, Vol. 19, No. 21 Peng et al.

tency, which was comparable to ciprofloxacin against Gram-posi-

OH R OH tive bacteria [213]. In addition, the results of DNA cleavage studies
showed that compound 101 was also quite active against Es-
cherichia coli, which was in accordance with the conclusion of
bioactive evaluation.
O OO O 6.2.3. Polysubstituted Coumarins as Antibacterial Agents
O
Triazole-based derixvatives display a broad spectrum of bio-
R= logical activities, and thus have been attracting special attention
97 [214-218]. The introduction of triazole ring is able to effectively
O accommodate the physicochemical property and bioactivity. Cou-
marin bis-triazole compounds exhibited stronger antibacterial effi-
S ciency than their corresponding mono-triazole derivatives. Particu-
OH larly, bis-triazole compound 102 with a (CH2)4 linker and its hydro-
NH
chloride gave a promising antimicrobial efficacy (MICs = 1-4
N
μg/mL), while the MIC values of standard drugs enoxacin and
NO2 chloromycetin were 1-16 μg/mL. Moreover, the anti-MRSA activ-
O O ity of coumarin triazole compounds was also comparable or supe-
98 rior to enoxacin and chloromycetin [219].
Researches have revealed that the antimicrobial potentiality of
gen bonds formed with the DNA gyrase B subunit. One is between osthenol is related to the branched alkyl group at C-8 position
the lactone O and Thr163, and another is formed by the m-NO 2 [220]. It is rational to conclude that O-aminoalkyl substituted 4-
oxygen atom and Arg136 [210]. methylcoumarins may also have strong antibacterial activity. Com-
It was reported that thiazolidinone compounds had a wide range pound 103a and hydrochloride of 103b, in which the O-aminoalkyl
of pharmacological activities. The change of the 2-aminothiazole substituent had N,N-diethylamino part, and acetyl group is present
linker in compound 98 into thiazolidinone bridge yielded derivative at C-8 (in 103a) or C-6 (in 103b) positions, demonstrated to be
99, this compound showed superior anti-Bacillus subtillis and anti- effective antibacterial molecules. Specially, the hydrochloride of
Staphylococcus aureus effects to standard antibiotic ciprofloxacin 103b could inhibit the growth of Bacillus subtilis and Bacillus
at the concentration of 100 μg/mL. The replacement of F atom by cereus bacterial strains with low MICs between 0.40 and 1.80
other substituents would decrease the antibacterial activity, this fact μmol/mL [221].
demonstrated that the potentiality of compound 99 should consid- A lot of isoindolone heterocycles possess a wide range of bio-
erably depend on the F atom at the 4-position of phenyl ring [211]. logical activities. Isoindolone substituted coumarin 104 with methyl
Literature has reported that coumarins with a halogen in 6- substitutions at 4- and 7-positions showed significant anti-Bacillus
position, no bulky substituents at 7-position and an acyl group on subtilis, anti-Staphylococcus aureus and anti-Escherichia coli po-
the p-position of the N-aromatic moiety possess effective activity tencies, which were comparable even superior to standard drug
against Helicobacter pylori. Encouraged by these indications, ana- ampicillin [222]. Structure-activity relationship showed that the two
log 100 was synthesized and displayed remarkable anti-Helico- methyl groups are necessary for the pronounced antibacterial activ-
bacter pylori ability. Its MIC values ranged from 2 to 8 μg/mL. ity.
Compared with reference metronidazole (MIC = 0.50-128 μg/mL), In addition, coumarins with mono- or di-methoxyl group in the
this coumarin might be a lead compound for further development benzene ring were able to enhance antibacterial ability when iodine
[212]. substitution was introduced [223]. 8-Iodo-5,7-dimethoxy coumarin
105 displayed antimicrobial property with MIC values < 100
O
CH3 μg/mL. Moreover, it showed comparable to or more than 14-fold
anti-Bacillus subtilis activity in contrast with standard drugs oxacil-
O
O lin, vancomycin and trimethoprim. Notably, compound 105 was
highly active against MRSA with similar potency to vancomycin,
N O O CH3 NH
the current drug to treat MRSA infection.
S HO
O The discovery of novel and potent anti-TB drugs is an urgent
need because no new drugs to treat TB have been successfully de-
O O veloped in the last 30 years. Design and synthesis of polysubstituted
F coumarin derivatives may be a feasible method due to the possible
99 100
influence of various substituents. 3D-Quantitative structure-activity
relationships (QSAR) CoMFA models could provide details on the
H fine relationship of structure and antitubercular activity, thereby
O N
offering ideas for structural modifications to improve the activity.
CH3 Naphthyl modified coumarin 106 showed 100% inhibitory efficacy
against Mycobacterium tuberculosis at the concentration of 6.25
O μg/mL [224]. However, preliminary molecular mechanics calcula-
tions showed that this compound was lack of planarity since the
H3CO hydrogen atom of 4-amino group confronted severe steric clash
with the one attached to C-5 position. The results indicated that
compound 106 might have the potentiality to be developed as an
O O effective anti-TB agent.
101
Quinazoline has been portrayed as an important heterocycle in
Phenols specially 3-substituted ones are associated with a vari- medicinal chemistry. Compound 107, a hybrid of quinazoline and
ety of biological properties. Coumarin 101, a modified product by coumarin ring, was identified as potent antibacterial agent against
3-substituted phenol, exhibited extremely active antibacterial po- both Gram-positive and Gram-negative bacterial strains with low
Coumarin Compounds in Medicinal Chemistry
N 4 O CH3 R1
N H3C
N
N N
O O
H3C
N O O O
N
4 R2
103a: R1 = H,
N 102
103b: R1 = COCH3, R2 = H
OCH3
HN
Cl
H3CO O O
I H3C
105
MIC values of < 10 μg/mL, which was similar to standard drug
ampicillin. Comparative study showed that the chloro substituents
at 6- and 8-positions of coumarin ring afforded the high antibacte-
rial activity [225].
Computer docking technique occupies a special position in drug
design and discovery as well as in the mechanistic study, which can
place a molecule into the binding site of the target macromolecule
with a noncovalent interaction, thereby predicting the suitable bind-
ing geometry for each ligand at the active site. Molecular modeling
studies showed that compound 108 with good antibacterial potency
and an internal coordinate mechanics (ICM, predicting favorable
protein-ligand complex structures with reasonable accuracy and
speed) score of -96.07 can form six hydrogen bonds with Asp-73
and another two ones with Thr-165 amino acid residues [226]. The
molecular docking consequence demonstrated that the formation of
hydrogen bonds with Asp-73 and Thr-165 amino acid residues
might be helpful for the antibacterial activity.
Isoquinoline alkaloids are an unknown class of heterocyclic
templates mimicking the core groups of natural products originated
from the basic framework of biologically active compounds. Cou-
marin-based isoquinoline alkaloid 109 could effectively cleave the
DNA of Staphylococcus aureus, thereby inhibiting the growth of
the pathogenic organism [227]. Unfortunately, it did not show any
interaction with the DNA of Escherichia coli, which indicated that
compound 109 might be inactive against Gram-negative bacterial
species.
Pyran fused coumarin 110 was found to have fabulous antibac-
terial activity (MIC = 20 μg/mL) when compared with the standard
drugs ampicillin (MIC = 100 μg/mL), chloromycetin (MIC = 50
μg/mL) and ciprofloxacin (MIC = 25 μg/mL), which deserved to be
further investigated as antibacterial agent [228]. Structure-activity
relationship revealed that the lipophilic methyl group and the fused
pyran nucleus could improve the antimicrobial effectiveness.
O
O CH3 O
H H
N N
N
H
S O
O O
108
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3901
CH3
CH3
O HOOC
O
R2 = COCH3 H3C O O
104
N
Cl
N N
O O
O O
Cl
106 107
7. ANTIFUNGAL COMPOUNDS
Invasive fungal infections, particularly those relevant to Can-
dida sp., pose a thumping and increasing threat to the health of
human beings [229,230]. Furthermore, the incidence of systemic
mycoses has been dramatically rising for the increased number of
immunocompromised patients who suffer from acquired immu-
nodeficiency syndrome (AIDS), the frequency of solid organ and
hematopoietic stem cell transplants, and the more aggressive che-
motherapy. In recent years, a large number of emerging treatments
have broadened the antifungal spectrum or improved pharmacoki-
netic and pharmacodynamic properties of bioactive compounds
with antifungal efficacy, which offer clinicians more effective and
less toxic alternatives to conventional antifungal drugs [231]. How-
ever, these new alternatives exhibit serious cross resistance, in par-
ticular for azole antifungal drugs [232-235]. Specially, the wide-
spread use of fluconazole leads to the rise of resistant Candida
strains [236,237] and consequently increases the mortality among
immunocompromised individuals [238]. Therefore, it remains an
urgent need to discover novel antifungal agents. Coumarin com-
pounds are well-known for their multiple bioactivities and the re-
searches on coumarins as antifungal agents have become more and
more active [239-241] although no effective coumarins as clinical
antifungal drug have been found until now.
7.1. Benzene Ring Modified Coumarin Compounds as Antifun-
gal Agents
Coumarin skeleton consists of a benzene ring fused a six-
membered lactone, thus coumarin compounds are structurally di-
verse. They can roughly be classified into benzene ring modified,
lactone ring modified and both benzene and lactone ring modified
coumarin derivatives except for fused coumarins. Only benzene
ring modified coumarin compounds are also called simple coumar-
ins, which are reported to be active against a collection of fungal
strains [242].
O O
CH3
N
OO N
109 CH2
110
O O
3902 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
Bunium incrassatum (Boiss.) Batt11. & Trab., an economically
important medicinal plant in Apiaceae family, is widely distributed
in the east parts of Algeria. Bioseparation of the roots of this plant
afforded two known coumarins scopoletin 111a and scoparone
111b for the first time. Bioactivity test revealed that the crude ex-
tract containing the above two compounds exhibited stronger activ-
ity against fungi than bacteria at the concentration of 8 mg/mL
[243]. In addition, compound 112 was found to be more active
against human pathogens, Aspergillus fumigatus and Mucor cir-
cinelloides than reference drug nystatin [244].
Bioactivity-guided fractionation of Baccharis darwinii, a tradi-
tional medicinal plant in Argentina, resulted in the isolation of di-
versinin 113, which displayed high fungicidal rather than fung-
istatic activities against Microsporum gypseum, Trichophyton ru-
brum and Trichophyton mentagrophytes with MICs of 15.60
μg/mL. Importantly, compound 113 showed a moderate efficacy
(MIC = 125 μg/mL) against Cryptococcus neoformans that could
cause life-threatening complication for immunocompromised hosts,
particularly for patients who had undergone transplantation of solid
organs [245].
7.2. Lactone Ring Modified Coumarin Compounds as Antifun-
gal Agents
In contrast with benzene ring modified coumarin compounds,
lactone ring modified coumarins still exert promising antifungal
activity and the related researches are relatively more active [246].
Imidazole ring is a vital and special pharmaceutical fragment in
azole antifungal drugs [247,248]. The incorporation of imidazole
ring into coumarin nucleus yielded compounds 114a and 114b.
Both of them showed significant activities against Candida krusei
and Candida albicans, almost equivalent to standard drug flucona-
zole at the concentration of 250 μg/mL [249]. Further studies mani-
fested that the chloro and bromo substitutions were very essential
for the outstanding antifungal potency. Thus, it is worthwhile to
investigate the effect of halogen on their activity.
Compound 115 was synthesized in the year of 1973, however
its antifungal activity has not been reported. Very recently, re-
searchers found that compound 115 displayed good activity in in-
hibiting the fungal growth in comparison to the standard antibiotics
nystatin [250]. Its two acceptors (the negative charge and the un-
paired electrons) might be the reason why this derivative had prom-
ising antifungal efficacy.
Some literature provided evidence that the introduction of elec-
tron withdrawing groups such as chloro and nitro moieties could
strongly change the antifungal ability of target compounds. Cou-
marin 116a with chloro moiety exhibited moderate antifungal activ-
ity (MIC = 15 μg /mL) against Aspergillus niger and Candida albi-
cans in comparison with fluconazole [251], while compound 116b
with nitro group could inhibit the growth of Candida albicans at the
concentration of 0.13 mg/mL even after 48 hours (Table 3) [252].
Therefore, further studies on the effect of electron withdrawing
groups on antifungal efficacy should be done.
7.3. Both Benzene and Lactone Rings Modified Coumarin
Compounds as Antifungal Agents
The functionalization of sulfamide has been proved to possess
much utility in medicinal chemistry and a number of sulfonamide
O
H3CO
O CH3
H2C
RO O O
111a: R = H 111b: R = CH3 112
Peng et al.
N
N
H R
N
N NH
NO2
O O
114a: R = 2-Cl O O
114b: R = 4-Br 115
antibacterial drugs have been used in clinic [253-257]. Coumarin-6-
sulfonamides with C-4 azidomethyl group 117a-b showed excellent
antifungal efficacies against Candida albicans, Aspergillus niger
and Fusarium oxysporum with MICs between 1 and 4 μg/mL,
which were 8- or 2-fold more active than fluconazole (MIC = 8
μg/mL) [258]. The polar azido group that was stable in physiologi-
cal conditions on the basic side chain at the allylic position with
respect to the biogenetically important C3-C4 double bond could
reduce the acidic character of coumarin antibiotics, thus might play
an important role in enhancing the fungicidal potency.
Mesoionic compounds have been of great interest to medicinal
chemists. On the one hand, these ring systems are composed of
delocalized electrons, and thus have the ability to electrostatically
interact with two complementary partially charged positions on
biomacromolecule receptor, such as a protein helix. On the other
hand, the mesoionic system is highly charged, yet net neutral elec-
trical character. Therefore, they are soluble to some extent in non-
polar or lipoid solvents. Mesoionic coumarin 118 exhibited good
activity towards Aspergillus niger and Candida albicans in com-
parison to griseofulvin, and the studies on its in vivo activity are
underway [259]. This kind of compounds has a great potentiality as
bioactive molecules compared to other organic entities due to their
mesoionic nature, good solubility and high sensitiveness.
Aspergillus fumigatus has the ability to survive in a multitude of
extreme environmental conditions due to its highly evolved sapro-
phytic mould with numerous adaptations [260,261]. Therefore, the
infective morbidity and mortality caused by Aspergillus fumigatus
is very severe. Coumarin-based quaternary ammonium salt 119 was
reported to possess pronounced anti-Aspergillus fumigatus activity
with MIC90 (90% minimum inhibitory concentration) value of
15.62 μg/mL [262].
Chloro-substituted coumarin 120 was reported to exhibit com-
parable antifungal activity in contrast with reference drug flucona-
zole. Meanwhile, it was found to have highly active DNA cleavage
ability towards Aspergillus niger at 25 μg [263]. Chromone modi-
fied bis-coumarin 121 displayed an MIC/MFC (minimum fungici-
dal concentration) value of 12.50/25.00 μg/mL towards the majority
of the tested fungal strains, which was superior or comparable to
standard drug griseofulvin [264].
From above, it can be concluded that coumarin compounds
modified at benzene ring, lactone ring as well as both benzene and
lactone rings exert quite potential antifungal activity in comparison
with clinical antifungal drugs. This suggests that coumarin-based
antifungal agents possess great development value in antiinfective
H3C CH3
O
O O O
H3C O O O
113
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3903

Table 3. Inhibitory Activities of Coumarins 116a-b against Fungal Strain

R1 N
R3
R2
116
O O

Substituents Activity
Compounds Fungal Strain Necessary Substituents
R1 R2 R3 MIC

116a Cl H p-Cl 15 μg /mL p-Cl

Candida albicans
116b OH CH3 p-NO2 0.13 mg/mL p-NO2

N3 HO
O H3C O
NH
S N CH3
O N N

R N O
O O CH3
CH3
118
117a: R = 3-CH3 117b: R = 4-CH3 O

CH3
CH3 O NEt2
H3C N
8 Cl
Br
CH3
O O O O 120
119 O O

OH R OH
O
H3C CH3

R=
H3C O O O O CH3 O
121

field, and more and more attention should be paid on related re-
searches.
8. ANTIVIRAL COMPOUNDS
Virus is a type of infinitesimal pathogenic microorganisms.
According to incomplete statistics, about 60% of epidemic infec-
tious diseases are caused by viral infection, which become a serious
threat to human health. In the more than 3600 kinds of viruses, at
least 1200 kinds of them can make a person get sick, in which the
classic representative ones are hepatitis virus (e.g. hepatitis C virus,
HCV), human immunodeficiency virus (HIV) and influenza virus
(e.g. influenza A, H1N1 subtype). Unfortunately, the treatment of
viral diseases is still lack of ideal drugs. To some degree, antiviral
agents can only inhibit the growth of virus instead of directly
destroying and killing them, otherwise they will also damage the
host cell. Importantly, there still are no antiviral drugs except for
vaccines to some viral diseases so far. In view of these obser-
vations, many medicinal workers dedicate their efforts to search for
effective antiviral agents. Coumarin compounds have shown large
potentiality as novel member of antiviral drugs [265,266].
8.1. Coumarin Compounds as Antiviral Agents Against HCV
Hepatitis C virus is a small enveloped RNA virus that belongs
to Flaviviridae family. About 3% of the current world people are
suffering from progressive liver disease caused by it and more than
100000 patients die of hepatitis C annually [267,268]. However,
current therapies can result in only 50-60% of the patients in a sus-
tained virological response. Thus there is an urgent need to discover
potent anti-HCV compounds.
Recently, benzimidazole derivatives have been reported to have
the ability to inhibit RNA polymerase of HCV NS5B. Based on this
observation, coumarin-based benzimidazole derivatives 122a and
122b were successfully synthesized by using methylenethio group
as the linker. Both of them possessed noticeable anti-HCV activity
with EC50 values of 3.40 and 4.10 μM, respectively. Furthermore,
compound 122b inhibited HCV RNA replication by 90% and 99%
respectively at the concentration of 5.00 and 16 μM with no effect
on normal cell proliferation. Comparative studies revealed that the
introduction of Br atom at 6-position on coumarin ring enhanced
HCV inhibition by 6.7-fold and also the selectivity by 2.9-fold.
Meanwhile, the attachment of benzimidazole-2-thione nucleus with
a pyranose improved the HCV inhibitory activity by > 9.4-fold and
also the selectivity by 6.7-fold [269]. From the data, these two con-
jugates may be considered as potential anti-HCV compounds for
further selectivity optimization.
The replacement of two carbon atoms in benzimidazole ring of
compound 122 by nitrogen atoms yielded their coumarin-based
purine analogs 123a and 123b. The EC50 value of compound 123a
3904 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
R2
R1 N
122a: R1 = F, R2 = H
N S
Br 122b: R1 = H, R2 =
O OAc
AcO
AcO
O O
against HCV was 2.00 μM, which increased the HCV inhibition by
29-fold in comparison to coumarin 122 [270]. Thus, compound
123a might become promising anti-HCV lead, and had plenty of
space for improvement as anti-HCV drug. Compound 123b, de-
rived from 123a by attaching a ribofuranose moiety onto purine
ring, showed a similar anti-HCV activity with EC50 value of 5.50
μM to its parent, which was also considered as an ideal lead with
moderate hydrophilic property. In addition, the free hydroxyl
groups on ribofuranose moiety allowed reduction of cytotoxicity
and increment of SI value [271]. These guidelines will be of value
to design and synthesize new conjugated compounds as anti-HCV
agents.
Tetrahydroisoquinoline substituted coumarin 124 was found to
be also active against bovine viral diarrhea virus with similarity to
HCV. When tested on the inhibitory activity towards HCV, com-
pound 124 displayed an EC50 value of 20 μM, which was in consis-
tent with the calculated one. The methyl substituent in the 4-
position of coumarin skeleton was favorable for its antiviral activity
[272]. Further study revealed that this compound was able to bury
well within the lining cleft of surface binding site of HCV RdRp.
CH3
CH3
O O O NH
N N
124
8.2. Coumarin Compounds as Antiviral Agents Against HIV
Since the first report in 1981, AIDS caused by HIV has spread
rapidly worldwide. Recently, the development of chemotherapeutic
strategies for AIDS has been considered as one of the most chal-
lenging scientific projects. Highly active antiretroviral therapy can
effectively suppress the HIV load and decrease the mortality in
AIDS patients. However, the emergence of drug resistance, the
unavoidable viral recurrence after drug treatments and the toxicity
of the therapy make the continued search for novel anti-HIV drugs
necessary.
It was reported that racemic 11-demethyl-12-oxo calanolide A
125a, which contained two chiral carbon centers at the C-11 and C-
12 positions than the natural product (+)-Calanolide A, had a com-
parable anti-HIV-1 activity with lower EC50 value (0.11 μM) and
better therapeutic index (TI = 818) in vitro. Compound 125a, de-
rived analog 125b by replacing one hydrogen atom with bromo
moiety, was identified to have much higher inhibitory potency and
therapeutic index (EC50 = 2.85 nM, TI > 10526) than its parent
125a against HIV-1 [273]. From this fact, it can be concluded that
modification of the nucleus at C-10 position may get drug candi-
dates with better activity against HIV-1.
With the continuous effort to develop potential anti-HIV-1
agents, derivative 125c was prepared through the further modifica-
tion of compound 125b at C-10 position by changing bromo group
into chloro moiety. Interestingly, analog 125c not only showed
Peng et al.
N
R
N N
123a: R = H
OAc N S
O
123b: R =
OH
OH OH
O O
good anti-HIV efficacy (EC50 = 7.40 nM) and high selectivity index
(SI = 1417), as well as a druggable profile with 32.7% oral bio-
availability in rat and tolerated oral single dose toxicity in mice, but
also was highly efficient in suppression of the wild-type and Y181C
mutant HIV-1 with EC50 values of 7.40 and 0.46 nM, respectively
[274].
Reverse transcriptase (RT) is considered as a target for the
treatment of HIV/AIDS due to its important role in the replicative
cycle of HIV. In the progress of treating AIDS, non-nucleoside
reverse transcriptase inhibitors (NNRTIs), which can bind to an
allosteric site of RT in a noncompetitive manner to cause distortion
of the three-dimensional structure of the enzyme and inhibit its
catalytic function, have become the key components in the combi-
nation regimens. s-Triazine modified coumarin 126 showed an IC50
and SI values of 1.07 μg/mL and 43 respectively against HIV-1.
Further studies manifested that the incorporation of aryl amino
containing p-substituted methyl group with lipophilic property led
to the selective inhibition of HIV-1 replication. Furthermore, the
improvement of lipophilicity (logP = 4.40) of target compound
might make them easily penetrate biomembrane and blood-brain
barrier and be taken up by cells [275]. Compound 126 is still valu-
able to be investigated deeply as novel NNRTI though it does not
show any activity against HIV-RT mutant strain.
H3C CH3 CH3 H3C O
O H3C O
N
N N O
H
O O O
R 125a: R = H 126
O 125b: R = Br
O O
125c: R = Cl
8.3. Coumarin Compounds as Antiviral Agents Against H1N1
Virus
Influenza, usually called as flu, is an infectious disease with
contagious, acute, febrile and respiratory properties caused by ribo-
nucleic acid viruses of Orthomyxoviridae family. It occurs season-
ally in epidemic and sometimes in pandemic proportions, and
reaches peak prevalence in winter which kills many people world-
wide every year. H1N1 virus is one of the subtypes of influenza
virus, which is a formidable problem. In particular, the outbreak of
swine influenza A (H1N1) in Mexico and other parts of the world
has led to issuances of pandemic alertness by the World Health
Organization [276]. Therefore, the identification of novel com-
pounds with inhibitory activity against H1N1 is urgent.
The medicinal plant Ferula assa-foetida L. that grows mainly in
Iran, Afghanistan and China is used as important remedy for the
well-known “Spanish Flu” (type A influenza, H1N1 subtype), and
its roots have been used for the treatment of many diseases [277].
Bioactivity-guided fractionation of the roots of F. assa-foetida led
to the isolation of coumarin 127 with good inhibitory efficacy
against H1N1 influenza virus. The IC50 and IC90 values of the natu-
Coumarin Compounds in Medicinal Chemistry
CH3 COOCH3
H3C
O O O
CH3
CH3 127
ral product 127 were 0.26 and 0.44 μg/mL, respectively, which
were more potent than reference drug amantadine (IC50 = 0.92
μg/mL, IC90 = 1.73 μg/mL) [278]. Contrast tests manifested that the
esterification of the methyl moiety at C-3' could enhance the anti-
H1N1 activity.
The search for alternative therapeutics to treat influenza is
needed owing to the emergence of resistant strains to currently
available drugs targeting NA enzyme. Recently, angelicin deriva-
tive 128a was identified as a high effective inhibitor against H1N1
virus in Madin-Darby canine kidney cell culture with IC50 value of
4.50 μM and 50% cytotoxic concentration (CC50) value > 25 μM.
Further modification of compound 128a resulted in its analog 128b
with 64-fold enhanced activity (IC50 = 70 nM) in contrast to 128a.
More importantly, compound 128b exhibited comparable potency
towards influenza A (H3N2) and influenza B virus strains to anti-
influenza drug zanamivir [279]. Preliminary mechanistic studies
suggested that coumarin 128 played an important role in the inhibi-
tion of ribonucleoprotein complex and should have the potentiality
to be developed further as anti-influenza drugs.
9. ANTIPARASITIC COMPOUNDS
Parasitosis is a common disease all around the world and some
parasitosises can grow into an epidemic disease in certain region,
which cause significant damage for society and economy. The dis-
eases associated with infectious parasites include helminthiasis such
as trematodiasis, nematodiasis and taeniasis, and protozoiasis such
as leishmaniasis, malaria, amoebiasis and so on.
Leishmaniasis is one of the most important parasitic diseases
worldwide due to its visceral form resulted from Leishmania dono-
vani. Antimonial derivatives, amphotericin B and pentamidine are
widely used as prevalent drugs for the treatment of this parasitic
disease. However, the emergence of resistant parasites in some
endemic area in India and Sudan forces researchers to develop new
antileishmanial drugs.
Phytochemical researches on medicinal plants are essential for
the treatment of leishmaniasis for that the use of folk remedies
based on these plants is a common practice. Natural coumarins
129a and 129b were isolated from Galipea panamensis in eastern
Panama and northwest Colombia. Both of them were screened
against axenic amastigote forms of Leishmania panamensis and
displayed EC50 values of 9.90 and 10.50 μg/mL, respectively.
Compound 129b was tested against intracellular amastigotes and
displayed an EC50 value superior to its CC50 value (> 33 μg/mL).
This result indicated that the in vitro activity of these two com-
pounds might be due to their general cytotoxic activity instead of
their selective action mode against Leishmania panamensis. Impor-
tantly, the leishmanicidal activities could be modulated by the in-
troduction of substituents at C-7 and C-8 positions of coumarin
backbone [280].
Helietta apiculata is a South American tree or shrub growing in
Paraguay, Brazil and Argentina, whose infusions of bark are used
as wound healings and leishmanicidal ulcers. Bioassay-guided frac-
tionation from Helietta apiculata afforded natural product 130,
which was active against promastigote forms of Leishmania sp.
with IC50 between 18.50 and 27.40 μM. The in vivo study of this
compound against Leishmania amazonensis in Balb/c mice indi-
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3905
CH3
O O O
128a: R1= CH3, R2 = Ph
R1
R2 128b: R1 = Ph, R2 =
O S
cated that the parasite burdens in the infected footpads were signifi-
cantly reduced (p < 0.001) by 98.6% after subcutaneous treatment
at 10 mg/kg for 14 days, which showed the same efficacy as refer-
ence drug N-methylglucamine antimonate [281].
Early researches have reported that natural 4-arylcoumarins
possess antileishmanial activity [282], some work investigated their
chemical synthesis. The synthesized 4-arylcoumarin 131 displayed
a significant activity against Leishmania donovani amastigotes with
IC50 value of 1.10 μM and SI value of 265. However, it exhibited a
weak cytotoxicity towards THP1 cells. Notably, its SI value was
nearly twice times than reference drug amphotericin B (SI = 140).
Further exploration revealed that the methoxyl groups at 6- and 7-
positions of coumarin skeleton were important for the anti-
Leishmania donovani activity and the parasite phagocytosis of
compound 131 might be through THP1 cells [283].
Malaria is another one of the most important parasitic diseases
in the world. However, its therapeutic management has become
problematic since the emergence of chloroquine-resistant strains of
Plasmodium falciparum [284]. Recently, trioxaquine comprising
1,2,4-trioxane-(4-aminoquinoline) moiety has been under clinical
trials as antimalarial agent [285]. This encourages workers to incor-
porate trioxane group into coumarin backbone with the aim to get
novel antimalarial hybrid. Compound 132 showed antimalarial
efficacy against chloroquine sensitive 3D7 strain of Plasmodium
falciparum and exerted moderate activity with IC50 value of 39.28
ng/mL in comparison to chloroquine (IC50 = 5.20 ng/mL) and arte-
mether (IC50 = 0.40 ng/mL). Structure-activity relationship dis-
played that the presence of bulky aliphatic group at C-8 position
trended to increase the antimalarial ability and the substitutions on
phenyl ring seemed to have no large effect [286].
Falcipain-3, belonging to the papain family, is one of the typical
cysteine proteases of Plasmodium falciparum. The search for falci-
pain-3 inhibitors is an important strategy to combat with malaria.
Imidazolone modified coumarins 133a-b were found to be effective
falcipain-3 inhibitors, whose docking scores were 51.18 and 51.32,
respectively. This might be explained for the fact that the amino
group on the coumarin ring, which was close to Cys51, was dis-
posed to form hydrogen bonds [287]. The predicted pIC50 values of
these two compounds were up to 8.03 and 5.21 for QSAR model
CoRIA, suggesting the concordance with the tested activity.
Additionally, hybrid 134 of chalcone and coumarin was also
reported to exhibit superior inhibitory potency against chloroquine
sensitive and chloroquine resistant strains with IC50 values of 3.10
and 4 μg/mL, respectively to reference drug chloroquine (IC50 =
22.30 and 230.10 μg/mL, respectively) [288]. Interestingly, com-
pound 134 did not show any toxicity against normal K562 cell line
even at concentration greater than 100 μg/mL. However, the re-
placement of benzene ring by furan ring resulted in loss of activity
(IC50 > 50 μg/mL).
Amoebiasis is a parasitic disease caused by ingestion of con-
taminated food or water containing cysts of Entamoeba histolytica,
which threatens public health in most parts of the world, specially
in tropical and subtropical regions with poor sanitary conditions and
contaminated drinking water. Thiosemicarbazone substituted cou-
marin 135 exhibited better antiamoebic activity (IC50 = 1.06 μM)
than standard drug metronidazole (IC50 = 2.63 μM), which might be
3906 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
H2C O H3C
O O
H3C
CH3
132
OH O
O O
developed as drug candidate for the treatment of amoebiasis. Nota-
bly, compound 135 showed > 80% viability at 3.125-200 μg/mL
when tested for toxicity using H9c2 cardiac myoblasts cell line
[289]. The results showed that the introduction of N-methylbenzyl
amine could enhance the antiamoebic activity.
10. ANTIINFLAMMATORY AND ANALGESIC COM-
POUNDS
Inflammation is a complex defensive phenomenon resulted
from humoral and cellular reactions of the body to any noxious
stimulus, which may vary from local to general response character-
ized by the accumulation of fluids and leukocytes. Pain, as an un-
pleasant and subjective sensation, is one of the classic signs of the
inflammatory process induced by different chemical mediators
released during this process leading to nociceptive sensitization
[290]. In acute and chronic inflammation, the inflammatory re-
sponse seems to be mediated by different physiological and immu-
nological mediators. Non-steroidal antiinflammatory drugs
(NSAIDs) are widely used in the treatment of various types of in-
flammatory conditions. All the NSAIDs share approximately
equivalent antiinflammatory efficacy and cause unwanted side ef-
fects such as gastrointestinal ulcers and hemorrhages, and this fact
frequently limits their therapeutical extent. Therefore, medicinal
workers dedicate their efforts to exploit new NSAIDs. Coumarin-
based NSAIDs have shown their large potentiality in the battle
against inflammation.
10.1. Heterocycle Modified Coumarins as Antiinflammatory
and Analgesic Agents
Heterocyclic compounds, which generally contain N, O, S etc.
heteroatoms in their cyclic structures, represent one of the most
active classes of compounds showing a wide spectrum of biological
activities [291-293]. Heterocycle-containing coumarin derivatives
have been found to exhibit potential antiinflammatory and analgesic
abilities [294,295], which encourage a number of researchers to be
engaged in the studies on coumarin-based antiinflammatory and
analgesic agents.
129a: R1 =
R1O O O
O CH3
R2 H3C
R2 = H3C
129b: R1 = CH3, R2 = O HO
O CH3
Peng et al.
O
O OH
O
O R N
N CH3
133a: R = H
O O 133b: R = Ph
O
CH3 N O O
H
HO O O
H H
N N

2 H3C N
134
S 135
Cyclooxygenase (COX) can catalyze the bioconversion of ara-
chidonic acid to prostaglandins, which exists two isoforms COX-1
and COX-2. COX-2 is mainly involved in inflammation condition,
thereby is considered as an important target of antiinflammatory
agents. Heterocycle modified coumarins 136a and 136b showed
moderate antiinflammatory and analgesic activities. Benzothiazole
substituted coumarin 136a was found to be active in 1 h of drug
administration, but started to decrease after 1 h as a consequence of
its metabolic instability. Docking studies on COX-2 revealed that
1,2,4-triazole substituted coumarin 136b with MolDock score of -
159.165 was highly active one, which could form eight hydrogen
bonds since the attachment of nitrogen heterocycle increased the
ability to form hydrogen bond. However, when heterocycle was
replaced by other substituents, the activity decreased, which indi-
cated that the heterocyclic substituents in 7-position of coumarin
nucleus played an important role in antiinflammatory and analgesic
activities [296]. Thus, it could be concluded that the introduction of
heterocycle is favorable for the good antiinflammatory activity.
Pyrazoline is an important five-membered nitrogen heterocycle
and a lot of pyrazoline derivatives have potent antiinflammatory
activity, even some of them entered in clinical application as
NSAIDs. The introduction of pyrazoline into coumarin nucleus
yielded derivatives 137a and 137b. Compared to standard drug
diclofenac, both of them exhibited significant antiinflammatory
activity in the model of acute inflammation such as carrageenan-
induced rat edema paw and chronic inflammation such as adjuvant-
induced arthritis. As respect to in acetic acid induced writhing and
yeast-induced pyrexia model, compounds 137a-b also displayed
significant analgesic and antipyretic activity along with minimum
ulcerogenic index in comparison to aspirin. Importantly, these two
compounds did not show toxic effects at dose up to 2000 mg/kg.
The electron-donating group at 5-position of pyrazoline ring played
a vital role in antiinflammatory and analgesic activities [297].
Pyrazoline modified coumarins 138a-b were synthesized and
assayed for their antiinflammatory, analgesic and antipyretic activi-
ties. In antiinflammatory aspect, they gave 18.85% and 17.06%
inflammatory reduction activity, respectively. In analgesic aspect,
OCH3
CH3 OCH3
CH3
H3C
CH3
H3C H3CO
O CH3
O O O
H3CO O O
130 131
Coumarin Compounds in Medicinal Chemistry
R CH3
R
NH
O O O O
N R2
136a: R = N
N N
S R1
O O
136b: R =
N
compounds 138a-b exhibited 41.23% and 36.94%, respectively
protection efficacy against writhing. In antipyretic aspect, com-
pounds 138a and 138b significantly decreased the temperature of
pyretic rats, and the temperature of rectum was 38.14 and 38.10

, respectively compared to the control group (39.24 ). Molecu-
lar modeling and docking studies indicated that the ICM scores of
them were -97.27 and -105.59, specially compound 138b could
form ten hydrogen bonds [298].
Pyrimidine is one of the most prominent structures found in
nucleic acid, which is fundamental building block for deoxyribonu-
cleic acid and ribonucleic acid. Pyrimidine derivatives play an es-
sential role in several biological processes and in the pharmaceuti-
cal science, and even form a number of useful drugs. The combina-
tion of coumarin backbone and pyrimidine ring afforded their hy-
brid 139 with
SH at 2-position of the pyrimidine moiety, which
exhibited comparable analgesic activity after 60 min of administra-
tion to reference drug analgin. Moreover, compound 139 could
significantly decrease the temperature (32.61
) of pyretic rats
after 3 h in contrast to 34.68 
in the control group [299]. In addi-
tion, aminopyrimidine substituted coumarins 140a-b also exhibited
good analgesic activity in comparison to standard drug diclofenac
in the acetic acid-induced writhing response model [300]. Further
studies revealed that the sulfydryl and amino groups at 2-position of
pyrimidine ring could enhance analgesic and antipyretic activities.
Previous literature has reported that furocoumarins are of great
importance as antiinflammatory agents. Furocoumarin 141 was
found to induce in vivo protective potency (65%) against car-
rageenin-induced paw edema, while reference drug indomethacin
only induced 47% protective efficacy at an equivalent dose. Impor-
tantly, compound 141 did not exhibit any ulcerogenic activity.
Structure-activity relationship showed that the
COOCH3 group at
4-position affected the antiinflammatory effect [301]. The results
prompt researchers to further develop and test novel angularly or
linearly fused coumarins as new inflammatory agents.
Oxadiazole is an imperative pharmaceutical fragment since a
number of oxadiazole derivatives exert multiple biological activi-
ties. In view of this, incorporation of oxadiazole into coumarin
skeleton may produce novel compounds with enhanced activity.
Coumarin 142 with oxadiazole ring exhibited excellent acute antiin-
flammatory activity (81.3% and 64.5% reduction) at 3rd and 5th h
after administration, respectively, which was comparable to stan-
dard drug diclofenac. Moreover, it also showed comparable analge-
sic activity (68% reduction) to reference drug acetylsalicylic acid
O
Cl
N N
O O
139 SH
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3907
O
O
N
N
N
HO
137a: R = 4-Cl 138a: R1 = OCH3, R2 = H
137b: R = 2,4-Cl 138b: R1 = N(CH3)2, R2 = 2,4-NO2
(69% reduction) in peripheral analgesic activity model. Notably,
compound 142 did not show toxic effects at doses up to 2,000
mg/kg and it possessed a less degree of ulcerogenic potentiality
than standard NSAIDs [302]. However, compound 142 induced
ulcer almost as equipotent as clinical diclofenac.
Since several 3-piperazine substituted coumarins were reported
to exhibit high bioactivity [303], compound 143 was prepared and
showed significant antiinflammatory activity in vitro. In car-
rageenan-induced pleurisy model in rats, it could not only reduce
the formation of pleural exudate, the infiltration of polymorphonu-
clear leukocytes, but also decrease the total number of inflamma-
tion cells, attenuate histological injury and reduce TNF-, IL-1,
MIP-2 and IL-8 release. Further investigation revealed that the
antiinflammatory effect of compound 143 might be realized
through inhibiting nuclear translocation of NF-
B antiinflammatory
cells from pleural exudates [304,305].
10.2. Other Substituents Modified Coumarins as Antiinflamma-
tory and Analgesic Agents
Literature showed that some non-heterocycle substituted cou-
marin derivatives also exerted exciting antiinflammatory and anal-
gesic efficacies [306,307]. Hydroxyl coumarin derivatives 144a and
144b were synthesized and investigated systematically for their
antiinflammatory effects both on the expression of inflammatory
enzymes iNOS and COX-2, and on the production of inflammatory
factors NO and IL-6 in activated macrophages. They could signifi-
cantly inhibit the production of LPS-induced NO with the percent-
age of more than 80% as compared to cells treated with LPS alone
at 100 μM. Meanwhile, compounds 144a-b suppressed the expres-
sion of iNOS effectively (more than 80%) when tested at 100 μM
and inhibited the production of IL-6 (more than 80%) at the concen-
tration of 100 μM. Particularly, neither of them exhibited any cyto-
toxic effect at 100 mM. Structure-activity relationship showed that
the phenyl moiety at 4-position was responsible for the inhibitory
activity against NO production and iNOS expression. However,
these two compounds could not inhibit the expression of COX-2 in
a significant manner [308].
Cannabinoid 2 (CB2) receptor is one of the subtypes of can-
nabinoid receptors, whose agonists are effective in chronic pain
models and possess potent peripheral analgesic activity. Thus, it is
rational to take CB2 receptor as a vital target for the treatment of
pain. Benzyl coumarin 145 was identified to be an effective CB 2
receptor agonist with a Ki value of 1.03 μM. Contrast tests sug-
NH2 H3CO O
N N
R
O O
O O H3C O
141
140a: R = Cl 140b: R = OCH3 CH3
3908 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
O OH
Cl
S O
NH
N H
O O N 142
R
OCH3
HO O O HC
3 O
144a: R = H 144b: R = F
gested that the presence of methoxyl group on benzene ring and the
exist of methyl moiety at position 7 of coumarin nucleus improved
its affinity with CB2 receptor [309].
It is well known that the incorporation of fluorine atom into
organic molecules, specially into heterocycles can lead to distinc-
tive consequences in their biological property. Coumarin 146 with
fluoro moiety displayed 76% inhibition of pain and 81% inhibition
of inflammation with good safety profile and low ulcer index [310].
Therefore, compound 146 may be served as new template in the
synthesis and development of potent therapeutic agents for the
treatment of inflammation and pain.
The poor water solubility of coumarin compounds is carking in
the development of new candidates or drugs. Excitingly, PEGylated
4,8-dimethylcoumarins 147a and 147b were reported to have good
solubility and exhibited lower IC50 values of 18.20 and 12.30
μg/mL, respectively for TNF-
induced ICAM-1 expression on
HUVECs than their monomers [311]. The enhancement in the ac-
tivity of the water soluble compounds 147a-b might also be attrib-
uted to their better permeability and the longer retention time inside
the human endothelial cells.
O O O O
O O
H3CO O O O
n n
CH3 O O
O
O
OH
147a: n = 19, m = 6
O O O O H3C 147b: n = 33, m = 5
CH3
11. ANTIDIABETIC COMPOUNDS
Diabetes mellitus is one of life threatening acquired metabolic
disorder syndrome due to the secretory change or the decrease of
insulin and is found in most of the countries in the world. It is char-
acterized by elevating blood glucose accompanying with metabolic
disorder of carbohydrate, fat and protein. Diabetes mellitus can be
mainly divided into two types: insulin-dependent and noninsulin-
dependent diabetes mellitus, while the latter occupies about 90%
ratio in diabetes mellitus, which is developed due to the effect of
sedentary lifestyle, dietary changes and genetic factors. The current
treatment of diabetes mellitus is including insulin and oral hypogly-
cemic drugs (metformin, sulfonyl ureas, glinides and glitazones).
Whereas, most oral hypoglycemic drugs may induce oedema and
weight gain, and are contraindicated in the setting of congestive
heart failure and in obese patients. Thus, many workers devote to
their researches to exploit novel oral hypoglycemic agents with
high hypoglycemic activity and low side effects. It can be believed
Peng et al.
CH3 F
O
N
Cl N N
HO O O 143
H
N
OCH3
F
O O
145
O 146
that a number of candidates based upon action on different molecu-
lar targets will replace the existing drugs soon.
Clausena harmandiana, as an endemic species that grows in
deciduous forests in Thailand, has shown some therapeutic activi-
ties in stomach ache and headache. Previous investigations of this
plant have isolated some coumarins with promising bioactivities
[312]. Coumarin 148, isolated from C. harmandiana, showed sig-
nificant increment in glucose uptake at 25 μM (425.62%, p < 0.001)
in L6 myotubes with a time and dose dependent manner. The glu-
cose uptake induced by 148 might be associated with the activation
of phosphatidylinositol 3-kinases [313]. Further comprehensive
pharmacological investigations towards this compound should be
carried out.
A series of N-acyl-3-coumarylamines were synthesized and
evaluated for their antihyperglycemic activity. Majority of these
compounds exhibited moderate to good decrease of postprandial
plasma glucose ranging from 19.5% to 32.8% in SLM and 3.26% to
25.4% in STZ models. Amongst, 6,8-bis tert-butylcoumarin 149
was found to be the most active one and exhibited decrease of post-
prandial plasma glucose by 23.3% in SLM and 25.4% in STZ mod-
els, respectively, in steptozotocin induced mice in contrast to met-
formin (12.9%, 20.5%) and glybenclamide (33.7%, 25.5%) [314].
Further studies on optimization and action mechanism of this com-
pound are in progress.
H Many physicochemical and pharmacological properties of syd-
nones with 1,3-dipole structural feature have been gained. The in-
corporation of this pharmacophore into coumarin nucleus afforded
m novel molecular templates with interesting biological properties.
Compared to the control enzyme inhibitor, chloro-substituted cou-
marin 150 with sydnone displayed stronger inhibitory activity
against
-amylase that could lower the glucose level in the blood
[315]. The electron withdrawing groups such as chloro substituent
was very essential for the inhibitory efficacy against
-amylase.
Glycogen phosphorylase,
-glucosidase and glucose-6-phos-
phatase have a crucial effect on the occurrence of diabetes. Re-
cently, glycosyl triazoles have been reported to possess
-
glucosidase inhibitory activity [316,317], thereby viewed as consid-
erabe potentiality as new antidiabetic agents. The combination of
glycosyl triazole with coumarin afforded their hybrid 151, which
showed promising inhibitory activities against
-glucosidase, gly-
cogen phosphorylase and glucose-6-phosphatase with inhibitory
percentage of 25.9%, 20.0% and 25% at the concentration of 100
μmol [318].
A lot of single heterocyclic compounds as antidiabetic mole-
cules have been exploited up to date. Some double bis-heterocyclic
coumarin derivatives were also found to be potential antidiabetic
drug candidates. Compound 152 with thiazole-thiazolidinone linker
Coumarin Compounds in Medicinal Chemistry
OH
CH3
H3C
H3C H3C
O O O O
H3C
H2C
CH3
148 H3C
CH3
CH3
O O
HO
N OH
O
N N
151
was significantly active (28%) in comparison to standard drug
(44%) for its hypoglycemic potency. Further studies showed that
the lipophilicity of the side chains and their electronegativity might
be responsible for the variation of hypoglycemic activity [319].
12. ANTIDEPRESSANT COMPOUNDS
Depression is a kind of serious and burdensome psychiatric
illness with high rates of chronicity and relapse, which may be as-
sociated with the arising stress and its effect on the cardiovascular
system. Pervasively, anxiety, low mood, loss of interest or pleasure
in normally enjoyable activities, cognitive impairment and suicidal
behaviors are the classic characteristics of depression [320].
Though a broad range of antidepressant agents are available on
market, a large proportion of patients suffering from depression do
not exhibit sensitive to or show only partial respond to the treat-
ment. Therefore, the clinical limitations as well as the adverse ef-
fects of currently used antidepressant drugs necessitate continuous
studies to develop novel, efficient and safe antidepressant agents.
Since coumarin derivatives have been reported to possess antide-
pressant activity [51], many synthetic efforts based on coumarin
scaffold are currently under investigation [321,322].
Corticotrophin releasing factor (CRF) gene may be an attractive
drug target for the development of effective antidepressant compo-
nents from traditional Chinese medicine. Psoralidin 153 from the
seeds of Psoralea corylifolia was reported to have antidepressant
effect without toxicity in the forced swimming test in mice [323]. It
could decrease immobility time and increase swimming deportment
without altering climbing behavior after oral administration for 3
consecutive days at dosage of 60 mg/kg. Moreover, natural cou-
marin 153 could ameliorate the elevations in serum corticotrophin
releasing factor induced by swimming stress in mice [324], and the
down-regulation of CRF gene transcription by 153 might be in-
volved in molecular mechanism [325].
It is established that different substituents on the coumarin ring
strongly influence the biological activity of its derivatives. Phenyl-
coumarins 154a-b exhibited impressive antidepressant activity in
CH3
CH3 O OH H
153
HO O O
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3909
S
H NH
N Cl
N N
O O
O
O O
150 Cl N O
CH3 149
CH3 N
S
O
NH
N N
O CH3
OH S
O O
O2N
OH 152
tail suspension test and forced swimming test at very low dose of
0.50 mg/kg in contrast to standard drug imipramine at the dose of
30 mg/kg. Compounds 154a-b produced their maximal effect at the
dose of 0.25 and 0.50 mg/kg, respectively, and did not show any
neurotoxicity in the rotarod test. Comparative study revealed that
the presence of bulky aliphatic chain like sec-butyl group at C-8
position decreased the antidepressant activity drastically, and the
change for the position of methoxyl substituent on benzene ring at
3-position of coumarin seemed to be able to modulate the pharma-
cologic potentiality of the newly synthesized coumarins [326].
Therefore, the detailed mechanistic studies and antidepressant re-
searches based on this scaffold are valuable.
MAO-A is an enzyme that can selectively catalyze serotonin
and norepinephrine neurotransmitters, and is considered as a phar-
macological target in the search of new agents for the treatment of
major depression. The fused coumarin 155 was evaluated for its
MAO inhibitor activity and showed selectively inhibitory property
against MAO-A with IC50 value of 2.28 μM, which was superior to
standards R-(-)-deprenyl (IC50 = 67.25 μM), iproniazide (IC50 =
6.56 μM) and moclobemide (IC50 = 361.38 μM). The strong effect
of compound 155 towards MAO-A might be related to the in-
creased availability of norepinephrine and/or serotonin neurotrans-
mitters in the synapses of the limbic circuits [327].
13. COUMARIN COMPOUNDS AS OTHER MEDICINAL
AGENTS
Epilepsy, characterized by excessive temporary neuronal dis-
charge, is a frequent neurologic affection. A lot of patients with
epilepsy do not respond well to currently available antiepileptic
drugs. Consequently, there is a real need to develop new antiepilep-
tic agents, specially those with new action modes to cover seizures
which are resistant to presently available drugs. Coumarin com-
pounds have been shown as a novel class of potential antiepileptic
agents. Compared to phenobarbital (50% paralyzed dose, PD50 = 16
mg/kg) at a dose of 30 mg/kg, thiazoline modified coumarin 156
provided equipotent antiepileptic activity with PD50 value of 95
mg/kg at a dose of 200 mg/kg. Moreover, compound 156 was de-
OCH3
O
H3C
OCH3
R
O O
O O
CH3 154a: R = H
154b: R = OCH3 155
3910 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
N N
O S
N O
O OH
O O N
H3C
CH3 156 N
H3C R O
157a: R = H 157b: R = 2-OCH3Ph
void of hypnotic and sedate properties and its LD50 value was
1453.78 mg/kg which was higher than phenobarbital [328].
Histamine is an intercellular chemical messenger, which has a
critical effect on several physiological processes. So far, four hu-
man G-protein coupled histamine receptor subtypes (H1–4) have
been recognized to mediate various actions of monoamine hista-
mine. Amongst, histamine H1 receptor has become an attractive
target for drug discovery for many years. Furthermore, H1 receptor
antagonists have been proved to be effective therapeutic drugs.
Piperazine compounds, as potent antihistaminic agents, have at-
tracted much attention [329-333] due to their antiemetic and an-
tivertigo effects, compatible antimuscarinic activity, low incidence
of drowsiness, as well as slow onset and long duration. The combi-
nation of piperazines and coumarins afforded their derivatives 157a
and 157b with potent antihistaminic H1 activity, which produced
competitive inhibition at low concentrations and noncompetitive
inhibition at high concentrations of histamine-induced contractions
of isolated guinea pig ileum. In addition, compound 157b had a low
ICM score of -99.68 against histamine N-methyltransferase, show-
ing the accordance with its high activity [334]. Molecular docking
displayed that these two compounds could bind with both pockets
of the enzyme. Interestingly, replacement of hydrogen atom on
piperazine ring by chloro moiety would abolish the activity, while
methoxyl group would significantly increase the efficacy.
It is well known that hyperlipidemia may induce other abnor-
malities such as oxidation of free fatty acids and lead to the forma-
tion of ketone bodies [335]. Statins represent the major class of
hypolipidemic drugs on the market. However, most patients still
experience adverse coronary events and undesirable side effects
despite of good statin therapy. Therefore, there is an urgent need to
discover new antihyperlipidemic drugs without severe side effects.
Indole and its derivatives are known to exert diverse bioactivities.
The incorporation of indole ring into coumarin skeleton afforded
derivative 158, which was found to possess potent antihyperlipi-
demic activity [336]. It could significantly decrease the plasma
triglycerides by 55%, total cholesterol by 20% and increase the
HDL-C/TC ratio by 42%, which were comparable with standard
drug atorvastatin at the same dose of 10 mg/kg (the levels of
triglycerides decreased by 63%, total cholesterol lowered by 14%,
and HDL-C/TC ratio increased by 35%). More importantly, cou-
marin 158 was devoid of cytotoxicity in normal cells. These results
suggested that compound 158 was a promising candidate in the
treatment of dyslipidemia condition. Structure-activity relationships
showed that the nature of substituents at 3-position played a pivotal
role in exerting its potency and the ethyl ester moiety was preferred
for pronounced activity.
14. COUMARIN-BASED SUPERMOLECULES AS MEDICI-
NAL AGENTS
Supramolecular chemistry is a rapidly rising hot-spot research
area [337], while supramolecular medicinal chemistry has become a
firenew direction of supramolecular chemistry in pharmaceutical
science [338]. Supramolecular drugs usually possess good safety,
low toxicity, little side effect, high bioavailability, strong target-
directivity, little multidrug resistence, excellent biocompatibility
and outstanding curative effect properties and so on, thereby show
great development value. So far, a number of supramolecular drugs
Peng et al.
H
CH3
O
O O
N O O
H 158
formed by two or more molecules through noncovalent interactions
have been extensively used in clinic. Excitingly, the oxygen het-
eroatom containing conjugated system enables coumarin com-
pounds to exhibit large dominance in the development of su-
pramolecular drugs [339,340]. They can bind with other molecules
through carbonyl oxygen atom of pyrone and various substituents
containing heteroatoms at different positions of coumarin skeleton
by the use of weak interactions like coordination bonds, hydrogen
bonds, ion-dipole, cation-
,
-
stacking and hydrophobic effect
as well as van der Waals force etc. Many investigations have
shown that coumarin derivatives in coordination with metal ions at
different positions can significantly enhance the biological activity.
This is generally, on one hand, attributed to the synergistic effect
between coumarin and metal ions that increases their lipophilicity,
on the other hand, is responsible for the change in structure due to
coordination, which results in the alteration of solubility, lipophilic-
ity, conductivity, dipole moment and cell permeability.
14.1. Coumarin-based Supramolecular Medicinal Agents Con-
taining Schiff Bases
Schiff-bases are a large class of chelating ligands in coordina-
tion chemistry [341], particularly those with N, O and S atom do-
nors, which have attracted much interest in the development of
supramolecular drugs due to the presence of imine group and the
similar structural characteristic to neutral biological system [342].
Coumarin-based Schiff-bases with the excellent coordinative prop-
erties of both coumarin and Schiff-bases are naturally regarded as
privileged ligands to coordinate with other molecules and ions for
the development of supramolecular medicinal agents. A lot of cou-
marin-based supermolecules with Schiff-base moiety have been
found to exhibit promising biological activity [343].
Copper(II) complexes, as one of the most common metal su-
permolecules, have been known for many years to be able to exert
outstanding efficacies against an array of bacterial and fungal
strains [344]. The metal Cu(II) complex supramolecule 159 was
formed by one CuCl2 inorganic molecule and two organic coumarin
Schiff bases, it exhibited MIC value of 1.56 μg/mL against Staphy-
lococcus aureus and Escherichia coli, which was equipotent to
reference drug norfloxacin. Whilst, it also displayed promising
antifungal efficacies towards Aspergillus niger and Candida albi-
cans with MIC value of 3.12 μg/mL in contrast to griseofulvin
(MIC = 1.56 μg/mL) [345]. From the molecular structure, it was
obvious that the coumarin-Schiff bases acted as a tridentate ligand
coordinating through azomethine nitrogen, phenolic oxygen of
coumarin, and chlorine of pyridine moiety.
Coumarin-Cu2+ complex 160 with an appended thiadiazole ring
demonstrated to be a potential agent against Escherichia coli and
Aspergillus flavus in comparison to standard drugs gentamycin and
fluconazole [346]. Complex 161, a naphthalene-bridged bis-
coumarin Schiff bases coordinating with Cu(II) salt in 1: 1
stoichiometry, gave equipotent abilities (MIC = 10 μg/mL) against
bacterial strains Pseudomonas aeruginosa (MTCC 7837), Salmo-
nella typhi (MTCC 3216) and fungal species Aspergillus
avus
(MTCC 1883) in contrast with references gentamycin and flucona-
zole (MIC = 10 μg/mL) [347]. Copper(II) complex 162 was ob-
tained by the reaction of copper(II) acetate with coumarin-based
Schiff bases, and exhibited good anti-Candida activity. Its MIC50
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3911

N N SH CH3
Cl Cl N
N S

2
N Cu2+ N
O O O
O O N
2Cl Cu2+
N
O O O
O O

2
O O S N
159 160
2Cl N
CH3 H3C CH3 HS

value (50% minimum inhibitory concentration) was 0.70 μM, sug-
gesting comparable to the commercially available antifungal drug
amphotericin B (MIC50 = 0.70 μM) and several times more active
than ketoconazole (MIC50 = 4.70 μM). Furthermore, this complex
maintained its significant activity (65% growth inhibition) even at a
concentration of 1 μg/mL [348].
Thiosemicarbazone and its derivatives are an important class of
ligands for transition metal ions. Their complexes exhibit a wide
variety of biological activities including antibacterial, antifungal,
antitumor and antiinflammatory properties [349]. Complex 163
derived from thiosemicarbazide and coumarin possessed strong
antibacterial efficacies against Salmonella typhi and Pseudomonas
aeruginosa, and antifungal activity towards Candida albicans with
MIC value of 10 μg/mL, which was equivalent to standard drugs
gentamycin and fluconazole (MIC = 10 μg/mL) [350].
Two coumarin-derived thiosemicarbazones and one CoCl2 salt
could form supramolecular complex 164, it was reported to have
antibacterial activities against Gram-positive bacteria Bacillus sub-
tilis and Staphylococcus aureus, Gram-negative bacteria Es-
cherichia coli and Pseudomonas aeruginosa, but the efficacy to-
wards Gram-negative strains was superior to Gram-positive ones
[351]. Cobalt(II) complex 165 was also based on thiosemicarbazone
substituted coumarin, it was also highly active against the tested
bacterial and fungal strains with MIC value of 10 μg/mL. DNA-
binding studies showed that the growth inhibition of complex 165
against pathogenic organisms might be responsible for cleaving the
genomes [352].
Metal supramolecular complexes of 1,2,4-triazole derivatives
have been extensively investigated for many years. Coumarin-
derived 1,2,4-triazole Co(II) complex 166 was screened for its an-
timicrobial activity, and the results suggested that it was a promis-
ing antimicrobial agent, specially against fungal strain Cladospo-
rium [353]. In addition, metal Ni(II) complexes have been found to
play an important role in antimicrobial filed. A large number of
metal Ni(II) complexes exhibited outstanding antifungal activity.
Coumarin Ni(II) complex 167 with Schiff bases could effectively
inhibit the growth of pathogenic organisms by cleaving the genome
and displayed comparable activities (MIC = 10 μg/mL) against
Bacillus subtilis, Salmonella typhi and Candida albicans to refer-
ence drugs gentamycine (MIC = 10 μg/mL) and fluconazole (MIC
= 10 μg/mL) [354].
Coordination chemistry of lanthanides in biological system has
aroused much interest [353]. Some lanthanide complexes can be
used as efficient DNA cleavage agents with or without sequence
specificity. In view of these observations, a series of lanthanide(III)
complexes derived from coumarins have been prepared and evalu-
ated for their antimicrobial activity. Samarium(III) complex 168
was identified to be effective DNA cleavage agent, and exhibited

O I
O
O O
N
O H3C
2
CH3 O H3C O I
N N Cu2+
H3C I O CH3
CH3
2Cl Cu2+ N
O O

2 2CH3COO O
161
I 162 O

CH3
N H2O
H2O H2N S S NH2
S O
O2N HN O Co2+
Cu2+ HN NH
N O N N O
H2O
H3C O H2O H3C O H2O
N O CH3 H3C O
4Cl
O O2N HN Cu2+ 2Cl
O S
H2O 164
N
n
CH3 163
3912 Current Pharmaceutical Design, 2013, Vol. 19, No. 21 Peng et al.

HN CH3 H3C N CH3

N
HN
N S N H2O
S
O O N
OH O O
O O Co2+ O O Co2+ H2O
O O Co2+
2Cl 4Cl N
S N O H2O
N S
NH H3C
165 H2O n
H3C NH H3C 166 N N

O O O O

CH3 H3C
O
O H2O N 3Cl N
H2O N N
N O O
N Ni2+ N H2N X Sm3+ X NH2
Ni2+
O O N H3C
H2O O HO N X
2 X = O, S
O N
4Cl NH2
O
n
O 168
167

O O CO
O N N O O O CO CO

La3+ W
O O N CO
H3C O O CH3
N
2NO3 N
169 170
O

interesting antimicrobial potency against all the tested strains with
MIC values between 10 and 25 μg/mL [355]. Whilst, La(III) com-
plex 169 showed MIC values ranging from 10 to 25 μg/mL [356].
Interestingly, wolfram complex 170, which took Schiff base
modified coumarin and nitric oxide as ligands, was found to exhibit
potential in vitro radical scavenging activity towards DPPH, OH˙,
O2
and NO˙ free radicals [357] and to remain good antioxidant
efficacy in vivo. The antioxidant ability of complex 170 might be
attributed to the proper electron density distributed on the complex.
The studies on the free radical scavenging efficiency of other transi-
tion metal carbonyls thus are worthy to be done.
14.2. Other Coumarin-based Supramolecular Medicinal Agents
Ciprofloxacin has an extensive potentiality used as antibacterial
drug in clinic. Its transition metal complexes have shown a signifi-
cant enhancement in antitubercular activity. Copper(II) complexes
171a and 171b with one ciprofloxacin molecule and one fused
coumarin as ligands exhibited strong antimycobacterial activity.
Complex 171a was more active (MIC = 9.28 μg/mL) than standard
drugs streptomycin (MIC = 60 μg/mL), isoniazid (MIC = 20
μg/mL), ethambutol (MIC = 40 μg/mL) and rifampicin (MIC = 500
μg/mL), while the methoxylated coumarin complex 171b was com-
parable with the standard drug rifampicin [358]. The results mani-
fested that introduction of copper salt to form supramolecular com-
plexes should be advantageous in the design and development of
highly effective drug candidates for antitubercular therapy.
Recently, the discovery that clioquinol can attenuate AD symp-
toms in human clinical trials has incited a renewed interest in its
pharmacodynamics about the possible therapeutical action by the
chelation of Cu(II) ion in the brain. Complex 172 with both cou-
marin and clioquinol demonstrated an enhanced antibacterial activ-
ity in comparison to clioquinol [359]. Interestingly, complex 173,
which was obtained by the alteration of substituents on coumarin
ligand in complex 172, not only exhibited moderate antimicrobial
efficacy with MIC values between 25 and 50 μg/mL in comparison
to streptomycin and nystatin (MIC = 6-12 μg/mL), but also was
active against Mycobacterium tuberculosis H37RV with an MIC
value of 25 μg/mL, and possessed significant antioxidant potency
[360]. Additionally, coumarin metal complexes 174 were also iden-
tified to be effective antimicrobial agents [361].
It is well known that metal-based drugs have successfully been
used in the detection and treatment of a variety of diseases [362]
including cancers [363]. The typical representative is cisplatin, a
typical metal supramolecular complex of one PtCl2 salt with two
NH3 molecules, which has been widely used in clinc, specially in
the treatment of testicular cancer, with 70-90% cure rate. However,
the clinical success of cisplatin is limited by its significant side
effects, such as nausea, vomiting, severe nephrotoxicity, and geno-
toxicity as well as resistance. These stimulate the further researches
for other transition metal complexes with more effective activity
and less side effects. Silver(I) complex 175 with mixed ligands of
coumarin and bisphenanthroline could decrease the proliferation of
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3913

O
H2O
O
O Cl N
2
Cu2+ O 

O O Cu2+ OH
O H2O O
I
23 OH O O OCH3
R
F N
171a: R = H 171b: R = OCH3 N 172
H

2 
I O
OH O
O O Cu2+ O Cl O NH O

2
O
Br N
2 M2+ O
2Cl CH3
173
2
OH M = Co, Zn 174

O O

O
O O O
N
NO3
O O O O O O O O

N N Ph Nd3+ 3NO3 Ph Nd3+ 3NO3 Ph

Ag+
HO O O O O OH
N N
O O O

175 176

HepG2 cells in dose- and time-dependent manners with IC50 value
of 3.80 μM, almost four times more potent than cisplatin. Notably,
non-neoplastic hepatic cells appeared to be less sensitive to the
effect of complexes, and comlex 175 could decrease the synthesis
of DNA. However, it was not able to intercalate with DNA [364].
Further studies are underway to investigate action mechanism of
this complex. The structurally peculiar Neodymium(III) complex
176 was also found to be active against tumor cell lines SKW-3,
BV-173 and K-562 [365].
Obviously, coumarin-based supermolecules have exhibited their
great potentiality as medicinal agents, not only for the excellent
activity against bacterial and fungal strains, but also for the prelimi-
nary efficacy towards oxidative stress and cancer cell lines. These
exciting results will attract more and more researchers to investigate
coumarin-based supramolecular medicinal agents against other
diseases and make coumarin chemistry present a firenew prospect.
15. COUMARIN COMPOUNDS AS DIAGNOSTIC AGENTS
AND PATHOLOGIC PROBES FOR BIOLOGICALLY
IMPORTANT SPECIES
Biologically important species such as life-related ions, en-
zymes, thiol-containing biomolecules and so on are quite essential
for maintaining human health. Their abnormal level would lead to
uncomfortable feeling of human body. Therefore, the timely and
accurate detection of these biologically important species have
attracted much attention in recent years, which endues the design
and development of diagnostic agents and pathologic probes with
large potential applications in medicinal chemistry [366]. Coumarin
compounds are well-known for their large
-
conjugated system
with electron-rich and charge-transport properties. This special
structure makes coumarin-based derivatives be considered as poten-
tial small-molecule fluorophores in the discovery and exploitation
of diagnostic agents and pathologic probes, which are valuable for
monitoring a variety of biologically important species and bio-
chemical process in living cells. Commercial fluorophores derived
from coumarin scaffold such as Alexa 350 (177) and Alexa 430
(178) are widely used in fluorometric assays [367]. So far, a great
number of coumarin-based diagnostic agents and pathologic
probes have been actively investigated [368,369] and rapidly de-
veloped, and have gradually shown their valuable applications in
pharmacology, pathology and diagnostics. This section will
mainly focus on discussing the current researches and develop-
ments of diagnostic agents and pathologic probes derived from
coumarin for the detection of life-related ions, enzymes, thiol-
containing biomolecules and other biologically relevant species.
15.1. Coumarin-based Diagnostic Agents and Pathologic Probes
for Biologically Relevant Ions
Cationic and anionic charged species are ubiquitous in chemi-
cal, biological, medical, environmental, and industrial processes
[370]. Specially in human body, the importance of biologically
relevant ions can not be underestimated for the fact that many en-
zymes rely on ionic species for their functions and they can regulate
a diversity of biological processes. For instance, iron(III) plays an
essential role in oxygen uptake of heme, oxygen metabolism, and is
a cofactor in many enzymatic reactions [371]. Zinc is involved in
the metabolism process of nucleic acid and protein, and can pro-
mote the normal development of skin, bone and sex organ and
maintain the digestive and metabolic activities. Chloride is essential
in biological systems and participates in a number of physiological
3914 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
O NH(CH2CH3)3
N 4
H
O HN
OH NH3
CH3
HO3S
H2N O O
177
and cellular tasks like in regulating membrane potentials [372].
Iodine is an essential element in human life, whose function is ex-
erted by the effects of thyroxine, and it can promote the growth and
development, the synthesis of protein and the absorption and utili-
zation of a variety of nutrients. In view of these observations, it has
been attracting considerable interest in the design of synthetic host
systems for cations and anions for many decades. The oxygen-
containing heterocyclic structure and the large conjugated system of
coumarin skeleton endue coumarin compounds with unique ability
to construct supramolecular system by multiple noncovalent inter-
actions in supramolecular recognition, particularly as artificial
cation and anion receptors, which have exerted extensive applica-
tion prospect in clinical medicine [373].
Supramolecular recognition [374] to metal cation ions is impor-
tant for human health and a lot of achievements have been made in
clinical medicine. The development of structurally simple cation
receptors with high selectivity and excellent efficiency and sensitiv-
ity has become an extremely attractive and quite active research
branch in supramolecular chemistry. A great deal of literature has
revealed that the oxygen atom in conjugated backbone of coumarins
is beneficial for their recognition for cations, because the electron-
rich property of coumarin compounds enables them easily to coor-
dinate with various metal ions.
Copper, the third most abundant essential trace element after
iron and zinc in the human body, acts as a cofactor for many fun-
damental biological processes [375]. Under normal conditions, the
total copper content of an adult human body is 70-80 mg, but the
alterations of its cellular homeostasis are connected with various
diseases. Even if exposure to a high level of copper for a short time,
it still can cause gastrointestinal disturbance, while long-term expo-
sure can cause liver or kidney damage even severer diseases. There-
fore, the development of artificial copper receptors with high selec-
tivity, sensitivity and suitability for imaging is quite urgent [376]
and considerable efforts have been made [377]. Coumarin 179 bear-
ing a 2-picolyl moiety exhibited high selectivity and suitable affin-
ity towards Cu2+ ion in the presence of a variety of other common
heavy and toxic metal ions in aqueous solution with pH value rang-
ing from 4 to 10. Moreover, it was potent for the detection of Cu2+
ion in biological system due to its good water solubility, membrane
permeability and nontoxic nature [378].
Compound 180 was obtained by the incorporation of a cou-
marin fluorophore with the benzyl dihydrazone moiety. Along with
the careful adjustment of redox potential of the fluorophore and its
O
CH3
CH3 N
H N
N N
N O O
CH3 179
Peng et al.
SO3
CF3
O
H3C
N O O
H3C O
O
3 N
O
178 O
excited state energy, it became one of the brightest Cu2+ ion binding
compounds in aqueous media. Given the excellent sensitivity, high
selectivity, good water solubility and favorable spectroscopic prop-
erties, this coumarin could act as an efficient receptor for Cu2+ ion
in living cells [379]. Whilst, coumarin derivative 181 with
piperazine rigid linker and hydrazide functional group could not
only selectively sense Cu2+ ion over other metal ions in a ratiomet-
ric fashion, penetrate cell membrane, but also be employed as rati-
ometric fluorescence imaging agent of Cu2+ ion in the living cells
with low cytotoxicity [380].
Cadmium (Cd) is an inessential heavy metal element with high
toxicity for life. The exposure of Cd2+ ion for human beings is
mainly through the ingestion of contaminated food or water, and
inhalation of cigarette smoke. Bivalent cadmium ion is harmful for
many organs and tissues such as the kidney, liver, gastrointestinal
tract, brain and bone, and chronic exposure to Cd2+ ion is a cause
for cancers. So far, many synthetic receptors have been developed
and shown response to Cd2+ ion. Coumarin 182 exhibited excellent
selectivity towards Cd2+ ion over other transition metal ions includ-
ing Zn2+ ion in aqueous media. With good membrane permeability
and strong affinity for Cd2+ ion, this compound could provide accu-
rate and quantitative measurements of metal ion concentrations in
cells [381].
In contrast with cation receptors, the researches of coumarin-
based artificial anion receptors are relatively rare because of their
comparatively large ionic radius and severe solvation effects. How-
ever, anion receptors still have a vital influence on human health
through the formation of supermolecules by noncovalent interac-
tions with anions in living cells. Literature has reported that metal
ions play an important role in anion recognition, as they can repre-
sent the active site for anion interaction [382]. With the more con-
tribution to anion receptors, it is rational to suppose that their re-
searches will become more and more highlighted.
Nucleoside polyphosphates, as one of significant biological
anions, have great influence on various cellular events. They act not
only as ubiquitous energy currency in all living organisms, but also
as the activated substrates in many enzymatic processes. Thus, the
selective detection and clear elucidation of their roles in related
physiological events under biological conditions are of much im-
portance. Coumarin-Zn(II) 183 was a high selective anion receptor
for nucleoside polyphosphates based on turn-on fluorescence sens-
ing and binding-induced modulation of fluorescence resonance
energy transfer. It could be used to monitor the changes of ATP
H3C
N Ph
O O N
O O N
Ph N CH3
CH3 180
Coumarin Compounds in Medicinal Chemistry Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3915

Et2N
CH3
O H
N N
CH3 N O
N
N N O O
N O O H
O N
N NH2
CH3 NEt2
181 NH2 182
O

levels inside living cells, which was directly correlated with the
cellular energy level [383]. Relative further investigations of metal
complex 183 are currently underway.
Nitric oxide (NO) is an active signal-inducing messenger mole-
cule in immune systems. It plays a critical role in vasodilation, syn-
aptic activity, and neurotransmission, while misregulation of NO
production will lead to many related diseases such as cancer,
ischemia, septic shock, inflammation, and neurodegeneration. Ni-
troxyl (HNO) group, the reduced/protonated form of NO, is associ-
ated with the increase of cardiac contractility in both normal and
failing canine hearts. Coumarin-Cu(II) complex 184 could sensi-
tively and selectively monitor the levels of biological HNO. It
showed dual-response to HNO with both fluorescence and electron
paramagnetic resonance and could be used to monitor the changes
of HNO levels in living cells with low cytotoxicity [384].
15.2. Coumarin-based Diagnostic Agents and Pathologic Probes
for Enzymes
Enzymes belong to a large class of biological catalysts consist-
ing of protein, RNA or its complex, whose obligations are to cata-
lyze a variety of biochemical transformations with high efficiency,
specificity and mild reaction conditions. Organisms are made up of
various cells. However the activity of each cell depends on the exis-
tence of enzymes. Moreover, enzymes are the catalysts of body
metabolism and all the biochemical reactions, and many biochemi-
cal processes can be carried out only in the presence of enzymes.
Once enzymes are deficient or their syntheses are obstructed, hu-
man beings will suffer from various types of diseases. Therefore,
the development of useful detective strategy to probe the activity of
enzyme in living cells is of great importance. The usage of fluores-
cent probes [385] becomes one of the most pervasive methods in
biological sciences, in development of new drugs and in clinical
diagnosis of diseases due to their high resolution and sensitivity,
while coumarins are widely used as leaving groups in fluorogenic
assays of enzyme activities [386].
Protein kinases are one member of enzyme family implicated in
nearly every cell-based behavior. They can modulate the activity of
their target proteins through the phosphorylation of serine,
threonine and tyrosine residues. So far, a great number of kinases
have been discovered, one of which is cAMP-dependent protein
kinase (PKA), and the characterization of their roles is a highly
active research topic. Various approaches have been made to moni-
tor the activity of protein kinases such as by the mere presence of
enzyme, by the effect of small molecule modulators and by fluores-
cent probes. Coumarin-derived peptide 185 could form a complex
with fluorescent quencher and furnish a sensitive measure of kinase
activity. Moreover, peptide 185 could be phosphorylated in a
cAMP-dependent fashion and the phosphorylation was blocked by
a PKA inhibitor, which suggested that compound 185 might be
served as a selective PKA probe [387]. Given the fact that PKA
plays an important role in the dynamics mediation of mitochondrial
biochemistry, the ability of probe 185 to monitor protein kinase
activity should be helpful to assess the response of mitochondria
from both healthy individuals and patients with mitochondrial-
based disorders [388].
It is well known that fluorescence measurement at a single
wavelength is easy to be influenced by artifacts related to micro-
scopic imaging system. Ratiometric fluorescence measurement,
which can simultaneously record the fluorescence intensity at two
wavelengths and calculate their ratio, is a good approach to reduce
the influence of such factors. Fluorescent probe 186, appended a
peptide substrate for protein kinases, was formed by a sensor and a
phosphorylation target peptide sequence. It exhibited a shift of exci-
tation spectrum upon phosphorylation, which demonstrated the
ability for ratiometric measurement of kinase activity. Importantly,
peptide probe 186 could continuously monitor kinase-mediated
phosphorylation through intensity measurements at two wave-
lengths. The results revealed that probe 186 may be considered as
the basis of sensor-based phosphorylation probes for various pro-
tein kinases [389].
The phosphorylation and glycosylation of proteins are two
common mechanisms in biological system, and phosphatases and
various glycosidases are the major hydrolytic enzymes involved in
these processes. Thus, it is rational to take these two enzyme fami-
lies as important targets in biomedical study. Fluorescent molecule
187 was prepared with the attempt to develop a new probe which
could sensitively and simultaneously measure the activity of phos-
phatases and glycosidases. Probe 187, with excellent chemical sta-

N N

Zn2+ 4Cl Zn2+

N N
N N
N
N
N Cu2+
N
O HO O O 2Cl N
N
N HN
183
N
Et2N O O O Et2N O O 184
3916 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
O O
CH3 NH
peptide
N O O O
185
CH3
O P
N
H
187
HO O O
bility and good intracellular delivery ability, showed high sensitiv-
ity and selectivity for the detection of
-D-glucosidase and phos-
phodiesterase I activity in physiological fields [390].
Protein tyrosine phosphatases (PTP) are associated with numer-
ous disease states and a surprisingly broad array of acceptable scaf-
folds. The inhibition of PTP is a popular area in medicinal research.
PTP1B, one of PTP subtype, whose obligation is attenuating the
signaling of the insulin receptor, recently has also been reported to
be relevant with tumor progression, thereby, monitoring the activity
of PTP1B is quite valuable. Several species were produced and
evaluated as substrates for PTP1B. Amongst, coumarin-based ben-
zyl ester 188, in spite of no homology of the natural peptidic sub-
strate, manifested to be a surprisingly good substrate for PTP1B. It
showed nearly 7-fold better as substrate than 4-methylumbelli-
ferone phosphate. However, probe 188 was still 5-fold off the natu-
ral peptidic ones [391].
Salicylate hydroxylase (SHL), belonging to flavoproteins, can
catalyze the production of catechol, CO2 and H2O from salicylate,
NADH, and O2. SHL was usually used as signal generator and for
the electrochemical detection of NADH in electrochemical analysis
due to its high performance characteristics, and the mechanistic
kinetic property of SHL has been studied extensively. However,
electrochemical method requires a cumbersome enzyme immobili-
zation procedure. Therefore, the development of novel strategy to
monitor SHL activity is necessary. Compound 189, which consisted
of a salicylate moiety directly linked to a fluorogenic coumarin
through an ether linkage, manifested to be a latent fluorogenic sub-
strate for SHL, and the assay platform constructed by fluorogenic
probe 189 and SHL-coupled dehydrogenase was expected to be
applicable for the measurement of a broad range of important
physiological analytes for clinical diagnostics [392].
The distribution of phospholipids across the plasma membrane
of mammalian cells is asymmetric, which is critical for various
biological functions. Aminophospholipid flippase is one of the most
studied translocases to maintain phospholipid distribution, and can
selectively transport phosphatidylserine (PS). The development of
fluorescently labeled PS substrates for the aminophospholipid flip-
COOH
OH
CN S N
N
O O O 190
189
Peng et al.
H
N
NH N NH
Cd2+ 2ClO4 peptide
O
NH NH
186
OH O
O
OH
O O
OH
HO
P 188
O O O
O
pase is an exciting method to investigate phospholipid translocase
activity in living cells and tissue. Fluorescent PS-coumarin conju-
gate 190 was a new translocation substrate for probing the activity
of aminophospholipid flippase, which exerted bright fluorescence
and much better photostability than the control PS-NBD. It could
readily enter the cytosol of mammalian cell lines attributed to selec-
tive translocation through endogenous aminophospholipid flippase
in cell plasma membrane [393]. Comparative study suggested that
PS derivatives with charged and highly polar groups attached to the
2-acyl chain could not be translocated by aminophospholipid flip-
pase and this translocation process did not involve phospholipids
passage through a non-selective hydrophilic channel [394-396].
MAOs can catalyze the oxidative deamination of a number of
biogenic and xenobiotic amines in the presence of oxygen. They
have important effect on central and peripheral nervous system to
maintain the homeostasis of neurotransmitters and metabolize die-
tary amines and pharmaceuticals. A lot of efforts have been made to
develop a detective strategy to monitor the activity of MAO due to
their vital roles in neurological health and diseases. Fluorescent
probe 191 with a molecular switch for activity detection displayed
fluorescence intensity towards MAO-B more than 22-fold en-
hancement in comparison to MAO-A, which demonstrated its high
selectivity to MAO-B. It was worthy to note that the high sensitiv-
ity of compound 191 could directly monitor MAO activity in aque-
ous solution without adding other proteins or activating reagents
[397].
The proteolytic processes in organisms is stringently controlled,
and once disregulated, it will result in diverse diseases. Therefore,
accurate and rapid detection of activity of protease in vivo is a nec-
essary work for researchers to undertake cellular studies [398].
Nanoprobe 192 with a bifunctional fluorophore attached to both a
nanoparticle and a protease specific peptide substrate was capable
of rapidly and accurately monitoring protease activity. Notably, its
multiple fluorophores could be switched on by a single enzyme, and
through the use of different peptide substrates, the protease speci-
ficity was achieved [399]. Further studies in cellular and in vivo
contexts are currently underway.
H3C
O
N 8 O
N O CH3
CH3 NO O O 14
O
O HO O P O
O
H3N
Coumarin Compounds in Medicinal Chemistry
CH3
H3C
N O
O O O O
191
15.3. Coumarin-based Diagnostic Agents and Pathologic Probes
for Thiol-containing Biomolecules
Cellular thiol-containing biomolecules, such as cysteine (Cys),
homocysteine (Hcy), glutathione (GSH) play crucial roles in many
physiological processes [400] including gene regulation [401], cel-
lular growth [402] and maintaining redox homeostasis through the
equilibrium established between reduced free thiols and oxidized
disulfides. Abnormal levels of biothiols are significantly associated
with a wide variety of diseases such as cancer [403,404], athero-
sclerosis, obesity, inflammation and aging-related complications
[405,406]. Therefore, it is of great scientific interest to develop
efficient probes for the detection and quantification of biothiols in
physiological media for academic research and clinical applications
[407].
The fused coumarin probe 193 could emit fluorescence when
used to recognize to thiols through a Michael type reaction, which
was mediated by intramolecular charge transfer. Moreover, chemo-
dosimetric probe 193 could effectively and selectively recognize to
thiols, exhibiting a preference to Cys over other relevant biological
species [408]. However, its preference to Cys was time-dependent
and the reaction with intracellular thiol species could not be stopped
when the samples were prepared for analysis.
Electrostatic attraction is unique and powerful interaction in
biosystems for immobilization and biomolecular recognition [409].
Turn-on fluorescent probe 194 with appropriate water solubility and
typical polarity-sensitive property consisted of a coumarin fluoro-
phore and a substituted methyl pyridinium group through an unsatu-
rated ketone unit, which showed a fast colorimetric and fluorescent
dual response through reacting with thiol group by Michael addi-
tion. Furthermore, probe 194 displayed 115- and 36-fold faster
reactions with Cys than Hcy and GSH, respectively, and this might
be responsible for the electrostatic attraction between it and Cys.
Notably, this probe conferred selective covalent binding with the
Cys34 residue in bovine serum albumin (BSA), thus might be suit-
able for the detection of active thiols in living cells [410].
Hydrogen bond is another common noncovalent interaction
apart from electrostatic attraction. Fluorescent probe 195 could be
highly activated by an intramolecular hydrogen bond due to the
presence of hydroxyl group and exerted a rapid and ratiometric
response to biothiols both in vitro and in vivo, specially towards
GSH [411]. Further investigations of compound 195 as a probe for
GSH-related diseases are in progress.
It is well known that thiazolidines can be formed by the reac-
tion of aldehydes with the N-terminal group of Cys in organisms,
and this selective reaction has been used to label and immobilize
O O
H3C O O
CH3
H3C
N O
N O O Cl
CH3 194
193
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3917
O O O
H3C CH3
NH N OH
H H
NH N
O
O
192 O N O O
H
peptides and proteins. Coumarin-based fluorescent probe 196, with
salicylaldehyde moiety as reaction unit and coumarin skeleton as
signaling unit, was reported to be able to react with Cys and Hcy to
produce a five or six-membered ring, which was attributed to the
nucleophilicity of both the nitrogen and sulfur atoms of Cys and
Hcy. Naturally, probe 196 showed a high selectivity towards Hcy
and Cys for that other amino acids without the nucleophilic sulfur
could not form the ring compounds. Importantly, this probe re-
mained the ability to recognize Hcy in human blood in the presence
of other biological ions [412].
Nitro olefin, one of the Michael acceptors described as a ‘‘syn-
thetic chameleon’’, is very attractive due to the presence of nitro
group, which is strong electron deficiency and readily converted
into other functional moieties such as keto, cyano and amino
groups. The colorimetric and fluorescent turn-on probe 197 could
detect thiols based on the 1,4-addition reaction of thiols with nitro
olefin in aqueous solution and it demonstrated higher selectivity
towards Cys, Hcy and GSH than other amino acids with fast re-
sponse and stable signal over a wide pH range. Further studies indi-
cated that this probe could enter cells and make fluorescent labeling
for thiols in living cells [413].
Fluorescent probe 198, composed of a coumarin with a thiolate
directly conjugated to its extended aromatic
system, was found to
have the ability to reversibly, quantitatively and ratiometrically
measure the thiol-disulfide equilibrium of biological systems by
comparing the ratio of emissions following excitation at 370-380
and 448-458 nm. The reversible reaction of probe 198 with thiols
and disulfides endowed its potency to detect dynamic in vitro
GSH/GSSH ratios and monitor the reversible redox status of whole
cell lysates [414].
In addition, coumarin-based fluorescence turn-on sensors 199a-
b with a chalcone moiety exhibited highly selective response to
biothiols both in vitro and in vivo. Amongst, probe 199b was 12- to
60-fold more reactive towards thiols than 199a. This might be bene-
ficial from the proton donation by hydroxyl group of 199b to the
vinyl carbon near the carbonyl moiety, thereby making the reaction
site more prone to be attacked by thiols [415].
15.4. Coumarin-based Diagnostic Agents and Pathologic Probes
for other Biologically Relevant Species
Human body is a perplexing organism containing various bio-
molecules, organs and systems. Certainly, normal enzymes and
thiol-composing biomolecules occupy a predominant space in
healthy individuals. However, the ordered organisms must be
modulated by different kinds of biologically relevant species in
O O
CH3
CH3
O N N O O HO
CH3 195
3918 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
CH3
HO O O N O
197
196
H O CH3
N
S CH3
H3CO O O
198 199a: R = H 199b: R = OH
HS O O
good coordination. It is undoubted that other species in living cells
still have important effects on human health and the exploitation of
fluorescent probe for them is currently urgent.
Hydroxyl radicals are a type of biologically important reactive
oxygen species. It is involved in a variety of diseases by the damage
of DNA, proteins, or membrane lipids, which demonstrates the
importance of detecting hydroxyl radicals in living cells. Ratiomet-
ric fluorescent probe 200 was found to be superior to other fluores-
cent hydroxyl radical probes in terms of selectivity, stability and
cell membrane permeability to monitor hydroxyl radicals in living
cells [416]. It may be developed as a useful biological tool.
Oxidative phosphorylation comprises a series of electron trans-
port systems in mitochondria for the generation of ATP and now is
considered to be relevant with the production of reactive oxygen
species, apoptotic cell death and various diseases. In view of this,
the investigations for the mechanism of various mitochondrial
events attract much attention. With the introduction of nitroxide
radical moiety into a fluorophore scaffold, compound 201 was ob-
tained. It could target mitochondria and inhibit oxidative phos-
phorylation in living cells, thereby allow the direct observation of
redox reactions associated with the respiratory chain in the mito-
chondrial membrane system [417]. Thus compound 201 may be an
effective mitochondria targeted redox probe to monitor the electron
flow. Additionally, polarity sensitive probe 202 with benzothiazole
moiety could act as an indicator of biochemical processes in the cell
environment involving subtle changes of cell polarity after appro-
priate conjugation to biomolecules [418].
H3C
H3C
CH3 N
N O O H3C
200
CH3
H3C CH3
O N
N [422].
H CH3
N O O fluorescent probes for the label of proteins through noncovalent
201
The pharmaceutical applications of nanoparticles, a rapidly
growing class of colloidal carrier systems, have evoked increasing
interest in recent years due to their numerous advantages including
the possibility of controllable drug targeting and release, good
Peng et al.
CN S
NO2
O H3CO
N
H3CO O O 202
O
O
N 12
R H
CH3
N O O
203
CH3
O
O
CH3 NH
N
N O O
O
204
CH3
stability of loaded drug, high drug payload and low to non-existent
biotoxicity of the carrier and so on. Coumarin 203 was identified as
a fluorescence probe to localize nanoparticulate carriers in the cells
with low cytotoxicity, high lipophilicity and good anchorage into
solid lipid nanospheres. Moreover, it provided an accurate reper-
toire of drug uptake and precise, quantitative data in real time for
the elucidation of the complex process at intracellular drug delivery
and distribution [419].
Thiamin, namely vitamin B1, is a vital nutrient for human be-
ings. The pyrophosphate derivatives of thiamin play an essential
role in the stabilization of acyl carbanion intermediates associated
with carbohydrate and amino acid metabolism. The deficiency of
thiamin can result in beriberi and may be involved in type 1 and
type 2 diabetes. Maleimide probe 204 with a purified mutant bacte-
rial thiamin binding protein was capable of real-time detection to
thiamin and its phosphate in nanomolar range, thereby was useful
for clinicians, enzymologists and biosynthetic chemists in thiamin
assays [420].
Biogenic amines are a class of low-molecular weight com-
pounds, in which there is at least one primary amine group, and are
formed during storage and process of food by thermal or enzymatic
decarboxylation of amino acids. Their elevated level is an indicator
of food spoilage. Biogenic amines exert important physiological
functions. For instance, aliphatic polyamines spermine and sper-
midine are relevant to cell proliferation [421], while histamine may
be served as neurotransmitter and has a significant effect on gastric
secretion. Coumarin-based probe 205 showed a pronounced selec-
tivity to important biogenic amines in buffered aqueous solution.
Furthermore, this compound could be employed for the optical
O detection of gas phase amines when embedded in polymer matrix.
The favorable abilities of probe 205 for biogenic amines might be
CH3 responsible for the presence of both aldehyde and hydroxyl groups
Polymethine dyes are a large group of well-known sensitive
interactions. Coumarin-derived polymethine dye 206 exhibited
high fluorescence intensity and noticeable emission enhancement in
the presence of BSA and BSA/SDS mixture, showing its potential-
ity as fluorescent probes for the detection of protein. The methyl
indolenyl moiety in the molecular structure increased the affinity of
compound 206 to both native and denaturized proteins [423].
Coumarin Compounds in Medicinal Chemistry
OH O ing properties, whose fluorescent staining in central nervous system
H protein. Moreover, this biological stain could selectively stain the
H3C
N O O suggested that compound 209 could reflect the process of myelina-
CH3 205
OH O The replacement of fluorine atom in compound 209 by a bulk
H3C
N and highly water-soluble properties. It could not only selectively
O O CH3
206 H3C
Clearly, coumarin compounds have displayed their confessed
latent applications as diagnostic agents and pathologic probes for
the detection of life-related ions, enzymes, thiol-containing bio-
molecules and other biologically relevant species in living cells.
Though the researches of coumarin-based diagnostic agents and
pathologic probes are in their initial stage, it can be predicted that
their related investigations will become more and more active in
protecting human health.
16. COUMARIN COMPOUNDS AS BIOLOGICAL STAINS
Biological stains are a kind of compounds that can selectively
stain for nucleic acid, protein and lipids and so on in cells through
the interaction between dyes and biological molecules, and there-
fore the physicochemical properties of the biomolecules are particu-
larly important for exerting strong interaction with biological stains
[424]. Recently, the development of biological stains has attracted
much inerest for their widely potential application as fundamental
analytical agents in biological and medical aspects [425]. Coumarin
compounds can display strong fluorescence when stained with bio-
logical molecules, which provides their potential applications as
biological stains in bioscience.
Pyrazolo[3,4-b]pyridine derivatives are essentially aza analogs
of indazole that have received considerable attention due to their
significant biological activity. Introduction of pyrazolo[3,4-
b]pyridine into coumarin backbone afforded hybrid 207 with strong
photostability, which was comparable with standard 208. Com-
pound 207 was identified to be an effective biological stain with
good penetrability for cell membrane for that intense intracellular
blue fluorescence was observed in the cytosol of HeLa cells when
coumarin 207 was incubated with the concentration of 50 nM after
20 min, and it could specifically stain cytosol. The blue fluores-
cence might be originated from the aggregation of this stain [426].
The loss of myelin in the central nervous system leads to the
axonal damage along with the occurrence of multiple sclerosis dis-
ease. Restoring new myelin sheaths by either endogenous repair
mechanisms or exogenous source of myelinating cells to demyeli-
nated regions is a satisfactory method. However, these clinical trials
need the quantitative assess for any changes of myelin content in
vivo. Fortunately, coumarin 209 was found to be a sensitive and
Ph
N N
N
H2N
Et2N O O
207
Current Pharmaceutical Design, 2013, Vol. 19, No. 21 3919
specific lead myelin stain with promising in vitro and in vivo bind-
was comparable to immunohistochemical staining for myelin basic
myelinated nerves in the peripheral nervous system. The results
tion, thus could be used as intraoperative nerve mapping during
surgical procedures, which allowed surgeons to dissect diseased
tissues with an aim to preserve functions of normal organs [427].
Gd-containing complex afforded its analog 210 with hydrophilic
stain myelinated fibers in situ in myelin-rich white matter regions
like corpus callosum, striatum, and cerebellum after chemical stain-
ing of freshly frozen mouse brain sections, but also selectively lo-
calize in different brain regions in proportion to myelin content
once delivered to the brain. Moreover, coumarin 210 was capable
of being used to detect areas of reduced myelination in a LPC rat
model of focal demyelination [428].
O HN
O N N O
Gd3+ O CH3
O N N O N
3Cl CH3
O
O O 210 O
17. CONCLUSION AND OUTLOOKS
Summary for all the above mentioned, coumarin compounds
have been extensively investigated in medicinal chemistry, and
coumarin chemistry has become one of the most rapidly develop-
ing, increasingly active and specifically attracting highlights. Cou-
marin compounds have clearly exhibited overwhelming potential
applications not only as anticoagulant, antineurodegenerative,
anticancer, antioxidant, antibacterial, antifungal, antivirus, anti-
parasitic, antiinflammatory and analgesic, antidiabetes, antide-
pressive and other bioactive agents, but also as supramolecular
medicinal drugs, artificial ion receptors, fluorescent probes for
biologically important molecules and biological stains. A great deal
of effort has been made directly or indirectly towards the discovery
and development of coumarin-based drugs and some excellent
achievements have been acquired. Among the large number of
various researches of coumarin compounds in the whole range of
medicinal chemistry, the most important and successful develop-
ments mainly exist in the anticoagulant, antineurodegenerative,
antibacterial, anticancer and antioxidative fields. Particularly,
coumarins as anticoagulant drugs have been widely investigated
and extensively used in clinic for many years.
According to the current researches and developments of cou-
marins in medicinal chemistry, the research hotspots of coumarin
compounds in near future will possibly focus on the following as-
pects:
CH3
F N
F F CH3
O O O O O
208 209
F
3920 Current Pharmaceutical Design, 2013, Vol. 19, No. 21
(1) A great number of investigations will continuously contribute
to the discovery, extract, purification, identification and usage
of naturally occurring coumarins as medicinal drugs.
Natural coumarin compounds from plants, animals and micro-
organisms etc. are still one of the most important source of medici-
nal drugs with noticeablly less toxicity and side effects, and provide
plenty of structurally novel molecular templates for the design and
preparation of more potential coumarin compounds with various
bioactivities, excellent physicochemical and pharmacokinetics
properties.
(2) Rational structural modification and combinative strategy will
become unusually active in design and discovery of novel
coumarin drugs because the resulted target compounds can
helpfully improve bioactivities and/or exert different action
mechanisms beneficial to overcome drug resistances.
Structurally simple and electron-rich coumarin ring is an at-
tracting molecular skeleton, and not only is easily modified by vari-
ous types of functional groups, but also can be employed to com-
bine with other bioactive fragments or compounds to develop more
active compounds with good bioactivity and physicochemical prop-
erties, proper binding affinity with active site as well as low side
effects and biotoxicity. However, only simply introduction of other
groups into coumarin skeleton or combination of coumarin ring
with other pharmacophores is blind and inefficient, thus rational
design and high qualitative bioactive evaluation of novel types of
coumarin lead compounds with completely new structures by the
use of modern methods such as computer-aided design and high
throughput screening will become more and more important.
(3) The developments of coumarin-based supramolecular agents
will become an important direction in future.
It is well known that supramolecular drugs generally possess
many overwhelming virtues such as good safety, low toxicity, less
side effects, high bioavailability, strong target-directivity, weak
multidrug resistence, excellent biocompatibility and outstanding
curative effects and so on. Oxygen containing conjugated coumarin
compounds exhibit large dominance in the development of su-
pramolecular drugs. They can coordinate with other molecules
through carbonyl oxygen atom of pyrone and various substituents
comprising heteroatoms at different positions of coumarin skeleton
based on coordination bonds, hydrogen bonds, ion-dipole, cation-

,
-
stacking and hydrophobic effect as well as van der Waals
force etc. weak interactions.
(4) A lot of effort will be dedicated to the studies and applications
of coumarin compounds as artificial ion receptors and fluores-
cent probes for biologically important species and biological
stain to monitor timely enzyme activity, complex biological
events as well as accurate pharmacological and pharmacoki-
netic properties to afford better understanding of drug behav-
iors in living cells and to endue researchers with more rational
design of potential drug leads and candidates. This is resulted
from the excellent fluorescent capacities of coumarins based
on the electron-rich and good charge-transport properties of

-
conjugated system, which give them underlying devel-
opment value in the area of biologically detective techniques,
thereby serving better for the prevention and treatment of vari-
ous types of diseases.
Obviously, with the researches of coumarin-based derivatives
as potential drugs, ion receptors, fluorescent probes and biological
stains being studied in-depth, bioactive coumarin compounds will
undoubtedly be exploited rapidly to prevent, treat and probe various
diseases. The researches and developments towards coumarin-based
bioactive medicinal agents will become one of the most important
topics in medicinal chemistry for quite a long time. More and more
coumarin-based chemical drugs with better curative effects, strong
pharmacological and pharmacokinetic activities, less side effects
and toxicities, and effective ion receptors, fluorescent probes for
Peng et al.
biologically important species and biological stains will be success-
fully developed and enter in clinical use, which will undoubtedly
make remarkable contributions to protect the human health.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
ACKNOWLEDGEMENTS
This work was partially supported by National Natural Science
Foundation of China [No. 21172181, 81250110089, 81250110554
(the Research Fund for International Young Scientists from Interna-
tional (Regional) Cooperation and Exchange Program)], the Key
Program of Natural Science Foundation of Chongqing
(CSTC2012jjB10026), the Specialized Research Fund for the Doc-
toral Program of Higher Education of China (SRFDP
20110182110007), the Research Funds for the Central Universities
(XDJK2011D007, XDJK2012B026).
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Received: December 30, 2012 Accepted: February 19, 2013
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