Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, 6, 293-306 293

The Anti-inflammatory Effect of Coumarin and its Derivatives

D.J. Hadjipavlou-Litinaa,*, K.E. Litinasb and C. Kontogiorgisa

a
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki,
54124, Greece; bLaboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki,
Thessaloniki 54124, Greece

Abstract: Inflammation is the primary host defense mechanism against all forms of injury. Excessive or inadequate acti-
vation of the system can have serious effects, as can the failure of inactivation mechanisms.
Coumarins can reduce tissue edema and inflammation and inhibit prostaglandin biosynthesis, which involves fatty acid
hydroperoxy intermediates. It is to be expected that coumarins might affect the formation and scavenging of reactive sub-
stances derived from oxygen species (ROS) and influence processes involving free radical-mediated injury, as can flavon-
oids.
During these years a small number of (Q)SAR studies concerning coumarins as NSAIDs has been presented and re-
viewed. In this research we tried to examine the structure-function relationship for coumarins, presenting anti-
inflammatory activity. Coumarin (1), the prototypical compound presents anti-inflammatory activity. The hydroxyl-
aromatic substituted derivatives (5- or 6- or 7-hydroxy or the vicinal dihydroxy) seems to be potent inhibitors of lipoxy-
genase. Several synthetic derivatives simple or more complicated were found to be potent antiinflammatories/antioxidant
agents.
Keywords: Coumarins, antiinflammatories/antioxidant agents, structure-activity relationships.

INTRODUCTION bio-synthesis of eicosanoid second messengers. Receptor-

Inflammation
Inflammation is a complex stereotypical reaction of the
body expressing the response to damage of its cells and vas-
cularized tissues and it has two main components - cellular
and humoral. The cellular component involves the move-
ment of leukocytes from blood vessels into the inflamed tis-
sue. Various types of leukocytes are involved in the initiation
and maintenance of inflammation. The discovery of the de-
tailed processes of inflammation has revealed a close rela-
tionship between inflammation and the immune response.
Once leukocytes have arrived at a site of infection or in-
flammation, they release mediators which control the later
accumulation and activation of other cells. There are four
major plasma enzyme systems which have an important role
in haemostasis and control of inflammation. These are the
complement system, the clotting system, the fibrinolytic
(plasmin) system and the kinin system. Inflammatory media-
tors are soluble, diffusible molecules that act locally at the
site of tissue damage and infection, and at more distant sites.
The major constituent of cell membranes are phospholipids.
Cellular phospholipases, especially phospholipase A2 and C,
are activated during inflammation and degrade phospholipids
to arachidonic acid. Virtually all cellular arachidonic acid is
esterified in membrane phospholipids where its presence is
tightly regulated through multiple interconnected pathways.
Free arachidonic acid is a transient, critical substrate for the
*Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, School of Pharmacy, Aristotle University of Thessaloniki,
Thessaloniki, 54124, Greece; E-mail: hadjipav@pharm.auth.gr
stimulated release, metabolism, and re-uptake of free arachi-
donate are all important aspects of cell signalling and in-
flammation. Acute inflammation is mediated by granulocytes
or polymorphonuclear leucocytes, while chronic inflamma-
tion is mediated by mononuclear cells such as monocytes
and macrophages which can be further stimulated to main-
tain inflammation through the action of an adaptive cascade
involving lymphocytes (T cells and B cells) and antibodies
[1,2]. Two types of free radicals are produced by neutrophils,
macrophages, endothelial and other cells. The first type is
represented by reactive oxygen intermediates which are
formed in neutrophils by the activity of NADPH oxidase, the
enzyme of the respiratory burst. The second type includes
reactive nitrogen intermediates. The first member of them,
nitric oxide, is produced by nitric oxide synthase.
The enzymatic oxidation of arachidonic acid has been
shown to yield potent pathological agents by two major
pathways. Those of the prostaglandin (PG) pathway, particu-
larly PGE2, have been implicated as inflammatory mediators
for many years. The discovery and biological activities of
thromboxane A2 and prostacyclin as well as a destructive
oxygen-centered radical as additional products of this bio-
synthetic pathway now require these to be considered as po-
tential inflammatory mediators. Like PGE2, their biosynthe-
sis is prevented by nonsteroidal anti-inflammatory agents
(NSAIDs). More recently, the alternative metabolic route,
the lipoxygenase pathway, has been shown to yield a new
class of arachidonic acid oxygenation products, the leukot-
rienes, which also appear to be important inflammatory me-
diators. Unlike the prostaglandins, some of which play im-
portant roles as biological regulators, the actions of the

1871-5230/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

294 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4
lipoxygenase products appear to be exclusively of a patho-
logical nature [3,4].
NSAIDs are widely used for the treatment of pain, fever
and inflammation [5]. All of the NSAIDs are approximately
equivalent in terms of anti-inflammatory efficacy but also
cause untoward side effects (e.g., gastrointestinal disorders),
in a significant fraction of treated patients and this frequently
limits therapy.
Like aspirin, all other NSAIDs such as ibuprofen, keto-
profen and naproxen develop their mode of action by block-
ing cyclooxygenase. Therapeutic effects and side effects of
this class of anti-inflammatory drugs are closely related to
their biochemical mechanism of action. The common
mechanism of action of this broad class of drugs is believed
to be the inhibition of the enzyme cyclooxygenase and the
blocking of the synthesis of proinflammatory prostaglandins
[1].
The coumarins (known as benzopyrones) consist of fused
benzene and
-pyrone rings, form a large class of phenolic
derivatives occuring in green plants, as well as in fungi and
bacteria [6a, b].
Coumarin (1) was shown to be capable of reducing tissue
swelling due to several stimuli. For example, it reduces
edema in rodents caused by thermal damage [7] and it is
effective against other lymphoedemas [8, 9]. Although the
mechanism is not clear, it appears that coumarins do not
work by reducing capillary permeability. It is likely to be
transported through leaky microvessels into the tissue spaces
[10]. Coumarins and their protein carrier are phagocytosed
by macrophages, reducing extravascular protein. Another
plausible explanation for these effects, points to macrophage
activation and proteolysis due to released lysosomal enzymes
[11-12].
O while 5,7-dihydroxy-4-methylcoumarin (9) demonstrated
O
1
During the inflammatory process, phagocytes generate
the superoxide anion radical at the inflammed site and this is
connected to other oxidizing species such as HO.. Simple
coumarins were tested [13-14] in several systems involving
reactive oxygen species (ROS) to characterize their antioxi-
dant profile and it was found that several phenolic coumarins
possess a significant antioxidant ability scavenging peroxyl
radicals. As a consequence, coumarins might affect the cy-
clooxygenase and lipoxygenase pathways of arachidonate
metabolism [15].
Sixteen plant-derived and various synthetic simple cou-
marins presenting hydroxyl groups and other substituents
were tested for their antioxidant activity namely, in relation
to the ability to inhibit lipid peroxidation and to scavenge
reactive species, for instance, hydroxyl and superoxide radi-
cals, and hypochlorous acid [16, 17-20]. Several coumarins
have shown beneficial biochemical profiles in relation to
pathophysiological processes dependent upon reactive oxy-
gen species [16, 19, 21-24]. Radical scavengers, structurally
based on coumarin, have also been studied [25].
Hadjipavlou-Litina et al.
In the present review we aim to provide a revision of
research with particular interest on the anti-inflammatory
activity of coumarins. Particular emphasis will be given to
the published QSAR of NSAID as well as of coumarins with
anti-inflammatory activity in order to delineate the specific
common structural characteristics. We will not give particu-
lar interest to the preparation methods of coumarins since
several review articles [26-29, 16] considering their synthe-
sis has been published.
The one bullet-one target approach to drug design, where
compounds exhibit a single specificity in action and function
are generally the preferred design. However, there are multi-
ple classes of agents with antiinflammatory activity includ-
ing coumarins, flavonoids, steroids and antibiotics that are
multi-function with activity across taxonomic kingdoms. In
fact for numerous agents their antiinflammatory activity was
a secondary finding.
A. NATURALLY OCCURING COUMARINS
I. Hydroxyl-Substituted Coumarins and Corresponding
Ether Derivatives
7-hydroxy-[1]benzo[b]pyran-2-one (umbelliferone) (2)
presents a significant antiedema effect in the carrageenan
model. 6,7-Dihydroxycoumarin (esculetin) (3) was found to
inhibit lipoxygenase more strongly than cyclooxygenase.
Esculin (6-glucoside of esculetin) (4) selectively inhibited
lipoxygenase, but less strongly (IC50=290 μM) than esculetin
[30a,b]. Esculetin (3), daphnetin (5) and fraxetin (6) have
been recognized as inhibitors of the proinflammatory lipoxy-
genase and cyclooxygenase pathways of arachidonate me-
tabolism [31]. These three coumarins, along with 4-
methylesculetin (7) and 4-methyldaphnetin (8) were tested
on ionophore-activated rat leukocytes (a cell system that
expresses both cyclooxygenase and 5-lipoxygenase pathways
of arachidonate metabolism) and they were found to inhibit
selectively the proinflammatory 5-lipoxygenase enzyme,
high potency against cyclooxygenase. Scopoletin (10) is re-
sponsible for antiinflammatory effect [32, 33]. Esculetin (3),
fraxetin (6), scopoletin (10), scoparone (11), capensin (12),
prenyletin (13), a methoxy substituted derivative, 7-(3-
methyl-2-butenyloxy)-6-methoxycoumarin (14), 7-(2-hyd-
roxy-3-methyl-but-3-enyloxy)-6-methoxycoumarin (15) and
5,7-dihydroxy-6-methoxy-8-(3-methyl-2-butenyl) coumarin
(16) have been isolated from the roots of Bupleurum frutico-
sum L. The powdered root is used as antiinflammatory agent
[3]. Osthole (17) was tested in 5-lipoxygenase (5-LOX) [34]
and turned out to be moderate and selective 5-LOX inhibitor
(IC50=36.2 μM). Osthole was found to possess 14.17%
(±9.8) inhibition of mouse ear edema 0.5 mg/ear. 6-(3-
Carboxybut-2-enyl)-7-hydroxycoumarin (18) significantly
inhibited the carrageenan induced rat paw edema at a dose of
0.03 mg/kg p.o (Structures 1-14).
Four coumarins coumarsabin (19), 8-methoxycoumar-
sabin (20), siderin (21) and coumarleucasin (22) were found
to present in [35] preliminary studies anti-inflammatory
properties (Structures 15-22).
Prenyloxy coumarins are secondary metabolites com-
monly present in plants belonging to the families of Rutaceae
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 295

HO GluO

HO O O HO O O HO O O
O O

1 2 3 4

Me
Me
MeO
HO

HO O O HO O O HO O O
HO O O
OH OH OH
5 6 7 8

OH Me
MeO MeO MeO

HO O O MeO O O O O O
HO O O

9 10 11 OH 12

MeO

O
O O O

MeO O O

13 14

OH
MeO MeO

O O O
O O O HO O O

HO
15 16 17

R1 OMe
R3

CO2H MeO O O
HO O O
R2

18 19 R1=Me, R2=H, R3=Me

20 R1=Me, R2=OMe, R3=Me

21 R1=Me, R2=H, R3=H
22 R1=CHO, R2=OMe, R3=Me
296 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 Hadjipavlou-Litina et al.

and Umbelliferae. Several of these coumarins were shown to
possess valuable anti-inflammatory activities [36]. Nine new
7-geranyloxycoumarin derivatives differently substituted at
position 8 were semi synthesized. Their topical anti-
inflammatory activity was evaluated using the croton oil ear
test in mice as a model of acute inflammation. Auraptene (7-
geranyloxycoumarin) (23), its 8-methoxy (colinin, 24) and 8-
acetoxy (25) derivatives provoked 50% edema reduction,
compared to the reference compound indomethacin, a non-
steroidal anti-inflammatory drug (Structures 23-25).
O
O O
auraptene (23)
OCH3
O O
O
The antiinflammatory properties of heraclenin (29),
psoralen (30), imperatorin (31), seselin (32) and heraclenol
(33) were examined against the ear edema in mice produced
by TPA. The antiinflammatory activities of the structurally
related compounds 27 and 33 were dose-dependent. Psoralen
(30) and imperatorin (31) showed a dual response: lower
doses possess an antiinflammatory effect, while higher doses
induce a proinflammatory effect. Seselin (32) showed poor
dose response. The results suggested that the antiinflamma-
tory response depended on its individual substitution on the
aromatic ring rather than the coumarin skeleton itself [37].
Cedrecoumarin A (34) was found to inhibit luminal-
enhanced chemiluminescence of reactive oxygen metabolites
generated by human polymorphonuclear leukocytes activated
with opsonized zymosan (IC50= 3.2 μg/ml) and to scavenge
superoxide anions in a cell free system (IC50= 3.0 μg/ml)
suggesting thus anti-inflammatory activity [26,38] (Struc-
tures 26-34).

B. SYNTHETIC COUMARIN DERIVATIVES

24
I. Substituted Coumarin Derivatives
OAc
7-Formylcoumarin (35) was formed through the SeO2
O
O O oxidation of 7-methylcoumarin (36) and gave some imino-
derivatives like the oxime 37, the O-methyloxime 38, the N-
phenylhydrazone 39, the dihydrazone 40, the N-
25
methylhydrazone 41, the N-phenylimine 42 and the N-
methylnitrone 43. These derivatives along with coumarins
. Fused Coumarin Derivatives
35, 36 were tested for their anti-inflammatory activity by
Xanthotoxin (26), xanthotoxol (27) and marmesin (28) checking their ability to inhibit the induced carrageenan paw
were isolated from Afraegle paniculata and were tested (at edema (CPE) in rats. From these compounds coumarins 36,
100 mg/kg) for antiinflammatory activity following oral ad- 37, 40 and 41 possessed significant (55.1%, 58.5%, 54.0%
ministration to rats or mice. and 54.7% respectively) protection against CPE [39]. Indo-

O O O O O O OH O O O O
OMe OH O O
O
26 27 28 29

O O O
O O O O O
O O O O
O O
30 31 32 33
HO OH

HO O O

34
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 297

methacin was used as reference drug (47 % inhibition of

O
inflammation). Compound 37 (X = N-OH) was found to be R
O
the most active (58.6 %). It seems that the presence of an R
N
oxime group at the position-7 of coumarin system is very N H
promising for the presence of anti-inflammatory activity. H O O
O NH
The above results were used for the derivation of the fol- 45a,b
lowing equation (1): 44a,b
44, 45a : R = 2-COOMe
% CPE = - 0.002 (± 0.001) MgVol + 2.103 (± 0.257) (1) 44, 45b : R = 4-COOEt
O
n = 6, r = 0.914, r2 = 0.835, q2 = 0.499, s = 0.039, F1,4 = 20.7, R1 45 c: R1=H

= 0.05 N
d: R1=6-OMe
H CO2H e: R1=8-OMe
It seems that higher Molar Volume (MgVol) is correlated O O f: R1=6-NO2
with lower in vivo inhibition of inflammation (Fig. 1).
45c-h g: R1=6-Cl
Coumarin imino analogues 44a,b and coumarin deriva- h: R1=8-allyl
tives 45a-h were found to be potent antiinflammatory agents
and their activities were comparable to the corresponding of significant anti-inflammatory activity. Compounds 46a-d,
piroxicam, as a reference drug [40]. In carrageenan-induced 47a, 48a, 49a were tested for antiinflammatory activity [41]
rat paw edema assays, compounds 45g, 44b, 45b and 45h in the carrageenan-induced rat paw edema method. All the
were found most active with 54±6.5%, 51±5.05%, 48±6.51% compounds showed reduction in edema volume. Compounds
and 47±7.13% inhibition respectively (at doses of 10 mg/kg 47a, 46a and 44a were found to be the most active [87%,
p.o., piroxicam showed 57±6.61% inhibition). Structure ac- 81% and 80% inhibition respectively in 5 h in doses of 100
tivity analysis of the above results shows that the substitu- mg/kg, oral comparable with the standard drug phenylbuta-
ents at the position 2’ of the phenyl ring at the position 3 of zone (79%)]. These compounds were further studied in pellet
the coumarin system are significant for the anti- granuloma method and showed considerable inhibition of
inflammatory activity. On the parallel free carboxyl group inflammation. Compound 47a was the most active (64.6%
seems to play an important role in the increase of the in- inhibition, while phenylbutazone as a reference showed
flammatory activity. Other specific substitutions at other 64.74% inhibition) (Structures 46-49).
positions of coumarin system do not seem to be crucial for
the anti-inflammatory activity, instead of the replace of H at Among the compounds, compound 48c was found to be
position 6 of the coumarin ring with Cl (Structures 44-45). the most active (> 80 %), while the compound 48a was
found less active. A structure activity analysis showed that
Ghate et al. [41] presented new coumarin series of vanil- vanillin ethers present significant anti-inflammatory activity
lin ethers (with o-formyl or p-formyl group), unsaturated and the position of the formyl group (o- or p-) does not seem
cyanoesters and benzo[b]furanyl coumarins (Fig. 2) with to significantly influence the anti-inflammatory activity.

H3C O O
Me O O
O O 33 HON=CH
N-C+ NH2OH.HCl 34
-O H 40 MeNHOH.HCl SeO2

MeONH2.HCl
PhNH2
O C O O O O
MeON=CH
O O 35
PhN=CH H 32
39 MeNHNH2 PhNHNH2.HCl

O O
H2NNH2.HCl PhNHN=CH
O O
MeNHN=CH 36
38

O O CH=N-N=CH O O

37

Fig. (1).
298 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 Hadjipavlou-Litina et al.

MeO
CH2O CHO MeO

CH2O
O
OMe
R
O O OMe
R
46a-f O O R
O O
48a-f 49a-f

a : R = 6-Me a : R = 6-Me a : R = 6-Me

b : R = 7-Me b : R = 7-Me b : R = 7-Me

c : R= 5,6-Benzo c : R= 5,6-Benzo c : R= 5,6-Benzo

d : R = 7,8- Benzo d : R = 7,8- Benzo d : R = 7,8- Benzo

e : R = 6-OMe e : R = 6-OMe e : R = 6-OMe

f : R = 6-Cl f : R = 6-Cl f : R = 6-Cl

CN
CH2O CH=C
CO2Et
OMe
R
O O

47a,b

a : R = 6-Me

b : R = 7-Me

However cyanoester coumarin derivatives and benzofuranyl sults indicated that the synthesized coumarins interacted with
derivatives seem to be more potent. the stable free radical 1,1-diphenyl-2-picrylhydrazyl
(DPPH); products 53a, 54, 53a, 56 can inhibit in vitro prote-
Coumarin derivatives 50, 51, 53a,b, 54, 55a,b, 56 and 57
olysis and compounds 51, 54, 55a,b, 56 showed significant
were screened for anti-inflammatory activity in vivo using
inhibition at the in vivo experiments (54.0-64.6%) in com-
the carrageenan rat paw edema [42] and in vitro through
parison to indomethacin (53.3%). Compound 55b showed a
their antiproteolytic activity and their ability to inhibit
-
good overall profile of biological activity (Fig. 2).
glucuronidase and soybean lipoxygenase. The obtained re-
CO2Et N
O R
H N-OMe H O H C
C H
C C CO2Et
52 H
RC N O H
MeONH2.HCl Ph3P=CHCO2Et 49a,b

O O O O O O O O
56 50 51
53
OMe PhNH2
N R
49b
N H N-Ph O
O C H N Ph
N
49a,b
49, 53, 54, 55 a : R=Me
b: R=4-MeOC6H4
O O O O
54 55a,b
O O
57
Fig. (2).
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 299

Derivatives (58a,b, 59a,b), isoxazole 60 and oxadiazole O H O

(61) respectively [43] were screened for anti-inflammatory H
O
R'
activity in vitro through their antiproteolytic activity, the R N N Me R N N
interaction with DPPH and the ability to affect superoxide N
anion and to inhibit
-glucuronidase and soybean lipoxy- O H
O
genase. The compounds were found to interact with DPPH, H
but the order of this activity was not parallel neither with that
in the two in vitro series lipoxygenase and superoxide anion O O
scavenging activity, nor with the proteolytic assay (Struc- 62 a: R = Ph
O O
tures 58-61). 63a,b 63 a : R=Ph
b : R=Me
b : R=Me
R2 O

O O
R1 N R CO2Me
N O
N H R'
Ph N
O N
Ph N
MeO2C N
N
O O O O O Cl H
58a,b 59a,b
a: R1=R2= Ph a: R = CH3 O O
b: R1=CO2Et,R2 = H b : = Ph O O
65a,b 65 a : R'=Ph
64
b : R'=Me
Ph MeO
O O
N N N H
CO2Et H O- C=NNHR'
C+ N
Me

O O O O O O
O O
60 61 66 67a,b 67 a : R'=Ph
b: R'=Me

A series of 4-substituted coumarin derivatives [44] with

tetrahydroisoxazole ring (62a) and dihydropyrazole ring A S
(63a,b, 64, 65a,b, 66) and N-phenyl or N-methylhydrazones NOH
HN O
67a,b were evaluated in vitro for their ability to inhibit tryp-
N
sin,
-glycuronidase, soybean lipoxygenase and to interact A N
with the stable radical DPPH. Compounds 63b and 65a were
tested in vivo as anti-inflammatory agents in the rat car-
rageenan paw edema assay (11% and 43.6% inhibition re- O O
spectively in comparison to 53.6% inhibition for indometha- 68a-g O O
cin) (Structures 62-67).
69a,b
The synthesized compounds 68a-g, 69a,b were evaluated
for their ability to inhibit trypsin-induced proteolysis [15.3- 68a-g 69a,b
98.2% (0.1 mM) inhibition, while the standard salicylic acid
a:A=H a : A = Ph
presented 53.6% inhibition] and to interact with DPPH
[10.5-97.7% (0.1 mM) inhibition with the standard acetyl- b : A = Ph b : A = 4-MeC6H4
salicylic acid to be at 80.5% inhibition]. The same com-
c : A =4-Me-C 6H4
pounds were also tested in the carrageenan rat paw edema
assay and in the most of the cases were found to protect
against edema formation (54.7-87.6% inhibition) in a per- d:A= (cyclohexyl)
centage higher than the reference standard drug (indometha-
e : A = HOCH2CH 2
cin 53.6% inhibition) [45] (Structures (68-69).
f : A =EtOCOCH2
The 3-substituted thiazolyl coumarins 70a-f were tested
as inflammation inhibitors [46]. Compound 70d caused a g : A = Me2N
36% inhibition of inflammation in the rat paw edema test.
300 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 Hadjipavlou-Litina et al.

inhibition, 82-90%, in comparison to salicylic acid (56%)]

R
and the inhibition of soybean lipoxygenase (LOX) [signifi-
R' cant inhibition, 52-79%, in comparison to nor-dihydro-
guairetic acid (91%)]. The significant in vitro biological re-
HN
sults were confirmed by the in vivo carrageenan-induced rat
N 70 a: R=Cl, R'=H
b: R=Me, R'=H
paw edema model, where a potent inhibition of inflammation
S (37-55%) has been found (indomethacin, as standard drug,
c: R=MeO, R'=H
had 49% inhibition) (Structure 75).
d: R=Cl, R'=4-Cl
O O e: R=Cl, R'=5-Cl
O(CH2)3NH(CH2)nNH2
f: R=Me, R'=4-Cl
70a-f
75a: 4-sub st., n=2
4-Pyridylcoumarin derivatives such as 71, 72 were effec- b: 4-sub st., n=3
tive for treating inflammation and diseases mediated by O O c: 7-sub st., n=2
phospholipase A2 and free arachidonic acid [47] (Structures 75a-d d: 7-sub st., n=3
71-73).
Scopoletin (10), isoscopoletin (76), umbelliferone (2) and
N N 4-methylumbelliferone (77) were regioselectively hydroxy-
OH Et HO hex lated at the 3-position to give 3-hydroxyscopoletin (78), 3-
hydroxyisoscopoletin (79), 3-hydroxyumbelliferone (80) and
3-hydroxy-4-methylumbelliferone (81). At the same time
esculetin (3) and 4-methylesculetin (7) were formed [51]. All
O O O O
hept hept the above mentioned compounds were tested for their inhibi-
71 72 tory activities on 5-lipoxygenase. The activities of 3-hyd-
roxycoumarins (78-80), esculetin (3) and 4-methylesculetin
O (7) were higher than those of their precursors. 3-
Hydroxyscopoletin (78) showed the highest inhibitory activ-
ity [76% inhibition at 25 μg/ml (IC50=0.0070 μM)] (Struc-
F
tures 76-81).

S O O
HO
Ph 73

4-Heterocyclic substituted coumarin derivatives with 7- MeO O O

HO O O
phenylthio substituents like 73 were found to act as inhibi- 76 77
tors of leukotriene biosynthesis and as anti-inflammatory
agents [48]. MeO OH HO OH
A series of substituted 3-(benzylideneamino)coumarins
74a-q were evaluated for antiinflammatory activity against HO O O O O
MeO
carrageenan-induced edema in rats. Compounds 74g and
74c, at oral doses of 100 mg/kg, showed 75 and 60% 78 79
antiedematous activity respectively (phenylbutazone 58%).
[49] (Fig. 3). OH OH
R
NH2 R N=CH
+ CHO HO O O O O
HO
O O O O
80 81
74a-q
Compounds 82-85 were tested for their ability to interact
74 a: R=H j: R=4-OH with DPPH [52]. Coumarins 82, 84 found to have high inter-
b: R=4-F k: R=4-OMe action (70.9, 77.4% respectively), coumarin 83 interacted
c: R=4-Cl
d: R=4-Br
l: R=4-NO2
satisfactorily (50.3%), while compound 85 presented very
m: R=4-NMe2
e: R=3-Cl
n: R=4-NHCOMe
low activity (18.2%) in comparison to the standard drug ace-
f: R=2-Cl o: R=2-OH
tylsalicylic acid (80.6%) (Structures 82-85).
g: R=3,4-Cl2
p: R=4-OH,3-OMe The coumarin derivative 86 showed high degree of anti-
h: R=2,6-Cl2
i: R=4-Me
q: R=4-OH,3-OEt oxidant activity [53].
Fig. (3).
Cloricromene (87), a coumarin derivative, attenuated the
All derivatives 75a-d were tested as antiinflammatory degree of chronic inflammation and tissue damage associated
agents [50] via the in vitro interaction with DPPH (low re- with collagen-induced arthritis in rats [54]. (Structures 86-
ducing ability, 8-22%), the inhibition of proteolysis [high 87).
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 301

Me Me
II. Fused Synthetic Coumarin Derivatives
The dimethylangelicins 90, 90a were evaluated as possi-
ble antiinflammatories in vitro [52]. The test for interaction
H2N O O (MeCO)2N O O with DPPH showed very low activity (22.4% and 11.4%
inhibition respectively). The competition of coumarins with
OH OCOMe
DMSO for HO. generated by the Fe3+/ascorbic acid system,
82 83 expressed as the inhibition of formaldehyde production, was
used for the evaluation of their hydroxyl radical scavenging
activity. Compounds 90, 90a (0.01 mM) inhibited signifi-
Me Me cantly (53.6 18.7% respectively) the oxidation of DMSO (33
mM).

Me
PhHN O O Ph N O O Me

OH COMe OCOMe

84 85
O O O
O O O
Me
CH2COMe
H Me
Me
N N Me 90 90a
CH2O O O N
S O
The dioxolocoumarins 91 and 92a-c were tested for their
86
O
O O
ability to interact with DPPH [slight interaction 3.12-28%
O
(0.1 mM), 13-44% (0.5 mM) in comparison to acetylsalicylic
O Cl 87 acid (80.5%)], to compete with DMSO for hydroxyl radicals
[high competition (40-74.7%) for 91-93, no effect for com-
pounds 92a,c, 94, to inhibit the Fe2+-stimulated oxidation of
Recently Grimm et al. [55] presented a series of couma-
linoleic acid (22-50.7% inhibition of lipid peroxidation for
rin derivatives 88a-j with potent inhibitory activity against 5-
compounds 92a-c, 94. The dioxolanes 91 and 92a have been
lipoxygenase with structural characteristics identical with the
compound L-746530 (89) potent 5-lipoxygenase inhibitor. screened in vivo (0.01 mmol/kg) for their anti-inflammatory
activity using the functional model of carrageenan-induced
Lipoxygenase is a well known enzyme implicated in the bio-
rat paw edema. Both induced a 55-57.4% protection, while
synthesis of leukotrienes and in the catalysis of the initial
the reference drug indomethacin induced 47% protection at
steps in conversion of arachidonic acid to leukotrienes. Thus,
equivalent concentration [56] (Structures 91-94).
lipoxygenase inhibition can lead to the decrease of leukot-
riene-mediated inflammatory response (Structures 88-89). The [7,8]-fused oxazolocoumarin 95 [56] was examined
in vitro for the ability to interact with DPPH [89.5% interac-

F
F

O
O O
O R1 O O
O d : R1 = Et, R2 = 2-thiazolyl, R3 = 4-F-Ph
O OH R2 e : R1 = Et, R2 = 2-pyridinyl, R3 = 3-Furyl
OH
f : R1 = Et, R2 = Et, R3 = 3-Furyl
88a-c R 88d-g g : R1 = CF3, R2 = CF3, R3 = 4-F-Ph
R3

a : R = 3 -furyl
b : R = Ph
c : R = 4-F-Ph

F
F

O
N CN
F3C O
S O O h : R = 4 - Cl -Furyl
F3C i : R = 3-Furyl O OH
OH j : R = Ph
L - 746,530
88h-j
R
89
O
302 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 Hadjipavlou-Litina et al.

tion, better than the standard drug acetylsalicylic acid inhibition) than the standard drug indomethacin (57% inhibi-
(80.6%)] and in vivo using the carrageenan-induced rat paw tion).
edema [56.3% inhibition (0.1 mmol/kg), significant in com-
Calophyllolide (102) showed potent antiinflammatory
parison to standard drug indomethacin (57%) inhibition (0.1
activity in carrageenan-induced edema in albino rats
mmol/kg)] (Structure 95). (ED50=140 mg/kg,p.o. [58] (Structures 100-102).
Me Me
Me Me Me Me

O Me Me
O O O O O
O
O O O O O O O O O O O
Et R1 O O
R2
COOEt 100 101
91 92a-c 93

Me

O Ph
COOEt
N O O
O O

MeO O O
O O O
94 Me 95 O

Another series of angelicin heteroanalogues, in which the 102

furan ring was replaced by a 1-substituted pyrazole moiety
was synthesized [57] by the reaction of malonic esters 96a,b
with the enaminoketones 97a,b to dihydrocoumarins 98a-d
and subsequent aromatization by 5,6-dichloro-2,3-dicyano-p-
quinone (DDQ) to [7,8]-fused pyrazolocoumarins 99a-d.
The coumarins 99a-c were tested for anti-inflammatory ac-
tivity by carrageenan-induced rat paw edema model. Com-
pound 99a showed at a dose of 50 mg/kg p.o. an appreciable
anti-inflammatory activity in comparison to that of the in-
domethacin (5 mg/kg p.o.) used as reference compound [57].
It seems that the indazole nucleus at the positions 7 and 8 of
the benzene ring of the coumarin ring might correlated with
better anti-inflammatory activity (Fig. 4) (Structures 96-99).
The pyranocoumarins 100, 101 [52] were checked in
vitro for the ability to interact with DPPH [compound 100
showed high interaction (94%) in comparison to acetylsali-
cylic acid (80.6% interaction), while compound 101 had low
interaction (23%)]. The derivative 100 was examined for
anti-inflammatory activity in vivo using the carrageenan-
induced rat paw edema model and gave better results (63.5%
Khan and his group [59] have recently presented a series
of pyridine-fused benzofuranocoumarins from various 4-
bromomethylcoumarins. Coumarin derivatives have been
tested for their antiinflammatory activity in the carraggeenan
rat paw edema method and the percentage inhibition for in-
flammation was measured. Compound 103b (R = 7-CH3, R1
= CH3) shown significant inhibition of inflammation in two
different doses (200 and 300 mg/kg dose) 80.7 % and 88.7
%. Compound 103g (R= 7-CH3, R1 = CH3 ) was also found
very potent in two different doses (200 and 300 mg/kg dose)
89.0 and 96.3 %. Compound 103f (R = 7-OCH3, R1 = -
CH2CH3) presented 78 % inhibition of inflammation at 300
mg/Kg dose level. Structure-activity relationships declined
that both substituents R and R1 should be small and lipophilic
in order to have higher antiinflammatory activity. It is crucial
to be mentioned that these compounds present also signifi-
cant anti-microbial and antifungal activity, since natural an-
gular coumarins are known to be highly active against fungi
and microbes (Structures 103a-g).

O O
COOR' COOR'
O O O
CHNMe2 CH2(COOR')2 DDQ
96a,b
N N N
N N N
R R R
97a,b 98a-d 99a-d

97a: R=Me 96a: R'=Me 98, 99 a: R=Me, R'=Me

b: R'=Et b: R=Me, R'=Et
b: R=Ph
c: R=Ph, R'=Me
d: R=Ph, R'=Et

Fig. (4).
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 303

HO O a : R = 6-CH 3

O b : R = 5,6- benzo
O c : R = 6-OCH3
N d : R = 6-Cl
O 106
R1
R
O O R
103 O O

O a : R = 6-CH 3
103a-g R R1
b : R = 5,6- benzo
O
a 7-CH3 H c : R = 6-OCH3
CH3
d : R = 6-Cl
b 7-CH3 -CH3

c 7-CH3 -CH2CH 3
O 107
d 7-Cl H

e 7-Cl -CH3
R
f 7-OCH3 -CH2CH 3 O O

g 6-CH3 H
A series of Mannich bases 108 containing a 7-OH group
were synthesized and evaluated recently [61] as anti-
In a more recent publication Ghate et al. [60] presented a
inflammatories. Indomethacin was used as a reference drug.
series of biheterocyclic coumarin derivatives 104-107 with
Compounds 108j (R1, R2 = piperazine) and 108k (R1, R2 =
significant high in vivo anti-inflammatory activity. Com-
morpholine) were found to be very potent, 77.7 and 75 %
pounds 106a-d including the 4-hydroxy-coumarin group
respectively. Both compounds have a heteroatom at position
were found to be quite active (54 – 62 %) compared to the 8 of the coumarin system. It seems that the presence of a
anti-inflammatory activity of indomethacin (62 %). All the heteroatom is better correlated with the inhibition of inflam-
other compounds were found to be less active. The presence
mation. The biological data were evaluated in terms of a
of a 4-hydroxy coumarin group seems to be significant for
QSAR analysis (2) [61].
the presence of anti-inflammatory activity (Structures 104-
107). % CPE = - 0.101 (± 0.079) Clog P + 1.881 (± 0.142) (2)
2 2
n = 10, r = 0.723, r = 0.523, q = 0.170, s = 0.085, F1,7 = 8.6,
H3C O a : R = 6-CH 3
= 0.01
OH b : R = 5,6- benzo The anti-inflammatory activity is correlated with the hy-
c : R = 6-OCH3 drophilicity of the derivatives (expressed as negative Clog P
values) (Structures 108).
d : R = 6-Cl
O Psoralens in conjunction with UVA irradiation are suc-
104
cessfully used in the therapy of psoriasis. Körner [62] de-
scribed the synthesis and biological properties of 3-alkyl-
R and 3-aryl-(7-oxo-7H-furo[3,2-g]chromen-5yl]alkanoic acids
O O
(109). The inhibitory activity of the new compounds was
quite modest in comparison to other known inhibitors of 15-
CH3 CH3 a : R = 6-CH 3 LO and leukotriene B4 production. It has been shown that
O b : R = 5,6- benzo hydrophobic and bulky substituents on the furan moiety of
O
these compounds differently influence their dark – and
O c : R = 6-OCH3
photo-binding with DNA (Structures 109).
d : R = 6-Cl
DISCUSSION ON THE (Q)SAR RESULTS OF ANTI-
O 105
INFLAMMATORIES AND COUMARINS WITH
ANTI-INFLAMMATORY ACTIVITY
Different chemical structures have been found to possess
R
different anti-inflammatory activities. Inflammation is a
O O normal and essential response to any noxious stimulus,
which threatens the host and may vary from a localized re-
sponse to a more generalized one. In view of the complexity
304 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 Hadjipavlou-Litina et al.

and multitude of biochemical factors involved in inflamma- a hydrophobic space in a non – specific way (slope 0.6 ±
tory events, few general correlations of chemical structures 0.1). It is obvious that the substitution with chemical sub-
and physicochemical properties with biological activities stituents, which increase either the hydrophilicity and/or hy-
would be expected. Nevertheless some general features seem drophobicity, associated with steric interactions due to the
to be commonly associated with a large number of active introduction of bulky substituents produces potent anti-
drugs. However, these main features are not sufficient, but inflammatory compounds (equation 2). Steric factors are
they could reflect certain physicochemical requirements for obviously important. MgVol and CMR are two physico-
in vivo efficacy. chemical parameters expressing the overall volume/size of
the molecules. We found correlations with MgVol(equation
1) (structures 108).
O O O HO O O Electronic parameters indicative of dipole-dipole or
charge-dipole interactions, charge transfer phenomena and
NH N
R1 R2 hydrogen bond formation, are not found to govern antiin-
flammatory activity
CH3
108 b - l
Confusion arises in the role of heteroatoms which confer
108a
different degrees of specificity terms in potency and in the
quality of the biological response (structures 108). The most
R1 R2
common structural elements of clinically active drugs against
b Piperidinyl inflammation appeared to be nitrogen or a sulfur heteroa-
tomic system bearing one or two phenyl rings and at least
c CH2CH2 -Ph H
one carbonyl group [63]. From our present review, the het-
d n-pentyl H erocycles confer different degrees of specificity in terms of
potency and in the quality of the biological response, which
e i-butyl H have not been delineated.
f n-pentyl n-pentyl Several examples are known in which structural modifi-
g CH2-Ph H
cation of biologically active compounds have yielded ana-
logues of constrained molecular conformation without con-
h CH2CH3 H sequent loss of activity and such studies have provided use-
ful compounds. Coumarins incorporate the styryl-carbonyl
i Piperazinyl
moiety into a rigid framework. From this point of view
j Morpholinyl phenyl-butenones, as styryl carbonyls, are precursors of
coumarins. Several styryl carbonyl derivatives, including
k CH2CH2NH2 H cinnamic acids, possess anti-inflammatory/antioxidant activi-
l CH2CH2 CH2NH 2 H ties [49, 64].
-In a QSAR study for lead optimisation in the design of
coumarins as potent non-steroidal anti-inflammatory agents,
R3 a : R1 = Me, R2 = Me, R3 = CH2COOH it was found that substituents in the coumarin positions C4-
R2 b : R1 = H, R2 = Ph, R3 = CH2COOH and C7- contributed to the high activity [50].
c : R1 = Me, R2 = Ph, R3 = CH2COOH
d : R1 = Me, R2 = 4-MeOPh, R3 = CH2COOH -Classic and three dimensional (3-D)QSAR analyses of
O O O e : R1 = Me, R2 = 2,5-(MeO)2Ph, R3 = CH2COOH
radical scavengers, structurally based on coumarin, have also
R1 f : R1 = Me, R2 = Me, R3 = (CH2)3COOH
g : R1 = Me, R2 = tert-Bu, R3 = (CH2)3COOH been performed [25]. Two classical models with predictive
109 h : R1 = Me, R2 = Ph, R3 = (CH2)3COOH cross-validated r2 (Q2) over 0.96 indicated that the activity
i : R1 = Me, R2 = 4-MeOPh, R3 = (CH2)3COOH was attributed to the electronic C-OH and ELUMO, steric molar
j : R1 = Me, R2 = 2,5-(MeO)2Ph, R3 = (CH2)3COOH
k : R1 = Me, R2 = 2,4-(MeO)2Ph, R3 = (CH2)3COOH
refractivity (MR) and lipophilic log P. Three-dimensional
l : R1 = Me, R2 = 4-F-Ph, R3 = (CH2)3COOH quantitative structure activity relationship (3-D-QSAR) stud-
m : R1 = Me, R2 = Me, R3 = Me ies were performed by 3-D pharmacophore generation (Apex
n : R1 = Me, R2 = 4-MeOPh, R3 = Me 3-D) and CoMFA techniques.
o : R1 = MeO, R2 = H, R3 = H

Within this research we tried to examine the structure-
function relationship for coumarins, which exhibit anti-
inflammatory activity. Unfortunatelly there is no much evi-
dence on QSAR studies of NSAID- coumarins. On the con-
trary a review [63] was published dealing with the QSAR of
several groups of anti-inflammatory agents. Taking under
consideration these results and comparing them with the
herein presenting (Q)SAR findings on the anti-inflammatory
activity of coumarins, it is obvious that clog P plays a sig-
nificant part in the QSAR of the anti-inflammatory agents. It
appears that many of the molecules must be interacting with
CONCLUDING REMARKS
Coumarins are a group of heterocyclic compounds cur-
rently being of great interest due to their multi-function. Tak-
ing under consideration all the above described coumarinic
compounds with anti-inflammatory activity the following
observations were derived:
-Coumarin (1), the prototypical compound possesses an-
tiinflammatory activity.
-Naturally occurring coumarins and several fused cou-
marins isolated from plants extracts were found to be potent
The Anti-inflammatory Effect of Coumarin Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2007, Vol. 6, No. 4 305

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Received: October 03, 2007 Accepted: October 10, 2007