Med Chem Res
DOI 10.1007/s00044-010-9472-5
REVIEW ARTICLE
Biological importance of imidazole nucleus in the new millennium
Balasubramanian Narasimhan • Deepika Sharma •
Pradeep Kumar
Received: 16 September 2010 / Accepted: 8 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Imidazole nucleus is a constituent of many
bioactive heterocyclic compounds that are of wide interest
because of their diverse biological and clinical applica-
tions. This created interest in researchers to synthesize
variety of imidazole derivatives and to screen them for
their various biological activities viz. anti-cancer, anti-
viral, antiHIV, anti-protozoal, anti-mycobacterial, anti-
inflammatory, analgesic, anxiolytic, as well anti-diabetic
activities.
Keywords Imidazole  Anti-cancer  Analgesic 
Anti-bacterial activity
Introduction
The incorporation of imidazole nucleus, a biologically
accepted pharmacophore in medicinal compounds, has
made it versatile heterocyclic nucleus possessing wide
spectrum of biological activities. Moreover, imidazole
derivatives are structural isosters of naturally occurring
nucleotides (Starcevic et al., 2007), which allows them to
interact easily with the biopolymers of the living system
which is responsible for their numerous biological activi-
ties and functions. In this study, we have made an attempt
to collect biological properties of imidazole nucleus
reported in the new millennium.
B. Narasimhan (&)  P. Kumar
Faculty of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak 124001, India
e-mail: naru2000us@yahoo.com
D. Sharma
University Institute of Pharmaceutical Sciences,
Panjab University, Chandigarh 160014, India
MEDICINAL
CHEMISTRY
RESEARCH
Biological importance of imidazole nucleus
Imidazole as anti-cancer agents
Cancer is a malignant disease. It is characterized by the
uncontrolled proliferation of cells, which may be rapid or slow,
depending on the particular cancer. Benign tumors may grow
rapidly but may not be life threatening. That feature is reserved
to cancerous, i.e., malignant tumors. Malignancy is the ability
to invade surrounding tissues, resulting in their displacement
and ultimate destruction. If that were all that malignancy
entailed, it would be highly curable by intervention of two
modalities of treatment: surgical removal of the tumor and
radiation therapy. It is third peculiarity of cancer that accounts
for most of the mortality, namely, metastasis. Metastasis is a
process by which the primary tumors ‘‘colonize’’ new tumors
at sites distant from its point of origin. Cancer treated with
multiple anti-cancer drugs tends to develop cross-resistance to
many other cytotoxic agents to which they had never been
exposed. Such tumor cell resistance to chemotherapy is a
major problem in the treatment of cancer.
In light of above, in recent years, number of researchers
concentrated toward the development of novel anti-cancer
agents. The anti-cancer agents based on imidazole nucleus
screened in the new millennium are described here.
Tiazofurin (2-b-D-ribofuranosylthiazole-4-carboxamide)
is an oncolytic C-nucleoside with potent inhibitory activity
against inosine 50 -monophosphate dehydrogenase (IMPDH).
IMPDH catalyzes the conversion of IMP to XMP and it is the
rate-limiting enzyme in de novo guanylate biosynthesis.
Keeping this in mind, Franchetti et al. (2001) synthesized a
new C-nucleoside analogue of Tiazofurin, i.e., 2-b-D-ribo-
furanosylimidazole-4-carboxamide (imidazofurin) 1 and
screened for it anti-cancer activity. Results of study suggested
that compound 1 possess good anti-cancer activity.
 Med Chem Res

CONH2 In a study of novel vicinal diaryl-substituted 1H-imid-

azole analogues of Combretastatin A-4 (CA-4), it was
HN reported that two 1,5-diaryl CA-4 analogues viz. 4 and 5
N
have been found to be more cytotoxic than CA-4. More-
HO O over, a combined computational strategy consisting of
molecular mechanics, rigid docking and molecular
dynamics simulations has been used to investigate the
interactions of 1,5- and 1,2-diaryl-1H-imidazoles 4-
HO OH naphthalen-2-yl-1-(3,4,5-trimethoxy-phenyl)-1H-imidazole
1 4 and 4-(3-fluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxy-
phenyl)-1H-imidazole 5 with the colchicines binding site
Distamycin A is a natural antibiotic belonging to the of ab-tubulin that is recognized main biological target for
class of DNA minor groove binding drugs which binds combretastatins (Bellina et al., 2006).
reversibly to double helical of B-DNA with high selectivity
for AT-rich sequences containing at least four Adenine–
OCH3
Thymine (AT) base pairs, thereby, acting as an alkylating
agent. In search of better analogues of Distamycin A, H3CO OCH3
Baraldi et al. (2003) synthesized a-bromoacryloyl pyra-
zole, imidazole and benzoheterocyclic derivatives of
Distamycin A and evaluated them for their in vitro anti-
cancer activity against mouse leukemia L1210 cells. From
N
the synthesized compounds, compound 2 N-methyl-3-[1-
methyl-4-[1-methyl-4[4(a-bromoacrylamido)imidazole-2-
carboxamido]pyrrole-2-carboxamido]propion amidine hydro N
chloride exhibited high anti-cancer activity with an IC50
value of 1.53 ± 0.23 lM. Further, from SAR studies, they
concluded that the presence of the amidino moiety is not an
absolute requirement for biological activity of a-bromoac-
4
rylic derivatives of Distamycin.
Br

H
N OCH3
O
N
H H H3CO OCH3
N
O N N
NH
N

O NH

3
2 N

Kumar and Lown (2005) designed and synthesized novel F

pyrrole [2,1][1,4] benzodiazepine (PBD) dimers linked with N
pyrrole and imidazole polyamides using mercuric chloride
mediated cyclization of the corresponding amino diethyl H3CO

thioacetals. All the synthesized compounds were tested

against a panel of 60 human cancer cells and reported that bis- 5
PBD-imidazole polyamide 3 possess appreciable anti-cancer
activity. O
H3CO N
O O O
H H
N O N N NH O
3N N N
H H N
N O
OCH3
O

3
Med Chem Res
DNA intercalating agents, containing a planar chromo-
phore with two to four fused aromatic rings, represent a large
family of anti-tumor agents. In view of above, Li et al. (2007)
synthesized a novel series of pentacyclic naphthalimides
fused to an imidazole ring containing an unfused aryl or
heteroaryl ring and evaluated for their in vitro cytotoxicity
against P388 (murine leukemia), A-549 (human lung can-
cer), SMMC-7721 (human hepatoma), HeLa (human cervi-
cal carcinoma), and HL-60 (human acute promyelocytic
leukemia) cell lines. Among the synthesized compounds,
arylimidazonaphthalimides, 6-[(2-dimethylamino)ethyl]-2-
(4-methoxyphenyl)-9-methyl-3,8-dihydro-1,3,6-triazacyclo-
penta[b] naphthalene-5,7-dione 6 and 9-(3,4-dimethoxy-
phenyl)-5-(2-dimethyl aminoethyl)-8H-5,8,10-triazacyclo-
penta[a]phenalene-4,6-dione 7 were found to be most
effective compounds against HeLa and SMMC-7721, with
an IC50 value of 0.21 and 0.22 lM, respectively.
O
N
H3CO
N
N O
H N
O
6
O
N
H3CO
N
N
H N
H3CO
O
7
Congiu et al. (2008) synthesized a series of new 1,4-di-
arylimidazol-2(3H)-one derivatives and their 2-thione ana-
logues and evaluated in vitro for their anti-tumor activity
against the NCI human cancer cell panel. Compounds
bearing a 3,4,5-trimethoxyphenyl ring linked to either N-1 or
C-4 position of the imidazole core demonstrated an inter-
esting profile of cytotoxicity with preferential activity
against leukemic cell lines. Compound 1-(4-Chloro-phenyl)-
4-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-imidazol-2-one 8
exhibited a potent anti-tumor activity against human
T-lymphoid cells (MOLT-4) (GI50 = 20 nM) and SR
(GI50 = 32 nM) cell lines.
O
NH
N OCH3
Cl OCH3
OCH3
8
A series of novel amino-substituted xantheno[1,2-
d]imidazole derivatives have been synthesized and their
anti-proliferative activity has been evaluated against
human breast MDA-MB-231 cell line. In general, it was
observed that among the tested compounds those bearing
two basic side chains at 2- and 5-positions exhibited a
strong dose-dependent anti-proliferative activity. During
the study compound 2-(piperidine-1-yl)-N-[2-(piperidine-
1-yl-methyl)-11-oxo-1H, 11H-xantheno[1,2-d]imidazol-5-
yl] acetamide 9 emerged as the most potent one (Kostakis
et al., 2008).
N
HN
N
O
NHCOCH2 N
9
Bolos et al. (2002) synthesized Cu(II)-based metal
complexes by reaction of [Cu(dien)NO3]NO3 with 2-
amino-5-methylthiazole (2A5MT), 2-amino-2-thiazoline
(2A-2Tzn), imidazole (im), N,N0 -thiocarbonyldiimidazole
(Tcdim), 2-aminothiazole (2-AT), and 2-ethylimidazole
(2Etim). They tested all complexes for anti-proliferative
(cytostatic and cytotoxic) activity against a panel of cell
lines viz. HeLa, L929, HF29, and T47D. They further
reported that the complex (dien)Cu(B)NO3](NO3) 10 has
an activity against colon cancer cells and suggested that the
predilection of all these Cu(II) complexes for colon cancer
cells may have some clinical usefulness since there are few
drugs currently used in colon cancer with no significant
advantage over the standard 5-fluorouracil based treatment
schedules.
Huq et al. (2004a, b) synthesized four trans-planaramine
platinum (II) complexes in form of trans-PtL(NH3)Cl2,
 Med Chem Res

where L = 2-hydroxypyridine and 3-hydroxypyridine, R' R

imidazole, and imidazo(1,2-a) pyridine. All the synthesized N
O
compounds have significant anti-cancer activity against N
O
human ovarian cancer cell lines: A2780, A2780, NH2

A2780ZDO473R, the melanoma cell line: Me1058 and the H2N

Cu

non-small lung cancer cell-line: NCI-H460, specially N

O
O
trans-{imidazo(1,2-a)pyridine}(amine) dichloroplatinum N
(II) 11 was found to be significantly more active than R R'
cisplatin against cisplatin-resistant ovarian cell line A2780.
In continuation of their study, they further checked cell 12
uptake and DNA binding of synthesized trans-planaramine
Kennedy et al. (2006) reported the synthesis of triflate salts
platinum (II) complexes. The higher activity of compound
of some mono-cationic, octahedral ruthenium (II) complexes
11 against the cell line is reflected in the greater level of
containing two chelated maltolato-type ligands in conjugation
binding with DNA.
with two monodentate nitro-substituted imidazole ligands and
evaluated for their in vitro activity against the human breast
2+ cancer cell line MDA-MB-435S using MTT assay. Among the
synthesized compounds trans-[Ru(3-hydroxy-2-methylpyran-
4-onato)2(2-methyl-5-nitro-1H-imidazol-1-ethanol)2]CF3SO3
and trans-[Ru(2-ethyl-3-hydroxypyran-4-onato)2(2-methyl-5-
HN NH nitro-1H-imidazol-1-ethanol)2]CF3SO3 were shown to exhibit
2NO 3
- anti-cancer activity comparable to cisplatin.
C Estrogens are important in the growth of breast cancers in
H2 N B both pre- and post-menopausal women and its sensitivity in
breast cancer increases with patient age. Two general
strategies have been developed for the treatment of hor-
mone-dependent breast cancer. The first strategy is to block
estrogen receptor action by disrupting its interaction with
10 estrogen and activation by estradiol and second approach is
to block estradiol synthesis catalyzed by the cytochrome
P450 enzyme aromatase. Aromatase has been a particularly
attractive target for inhibition in the treatment of hormone-
N dependent breast cancer since the aromatization of androgen
substrate is the terminal and rate-limiting step in estrogen
biosynthesis. In view of above, Hackett et al. (2005) syn-
N thesized a series of 2-azole and 2-thiazole isoflavones as
potential aromatase inhibitors. From the study, it was
Pt observed that imidazole analogue 2-(1H-imidazol-1-yl)-7-
Cl methoxy-3-phenyl-4H-1-benzo pyran-4-one 13 is 23-fold
Cl
more potent than the corresponding triazole with an IC50
NH3 value of 0.77 lM and with apparent Ki of 0.68 ± 0.04 lM.

11 O

Sandbhor and Pritchard synthesized copper complexes

of 5-amino-imidazole ligands 12 and evaluated for their
anti-proliferative effects on the growth of B16F10 mela- O O N
N
noma cell lines. The results indicated that all the complexes
have IC50 values ranging from 8 to 15 lM. Further, they
have suggested that reduction of Cu?2 in complexes and 13
their subsequent interaction with cellular thiols may be the A series of long-chained diarylalkylimidazole and
possible mechanism for their anti-cancer activity (Sandb- diarylalkyltriazole were synthesized and evaluated for
hor and Pritchard, 2004). their inhibitory potency for aromatase activity in human
Med Chem Res
placental microsomes by Karjalainen et al. (2000) Among
the synthesized compounds, 4-[1-(4-cyanophenyl)-4-(4-
fluorophenyl)-1-butenyl]-1H-imidazole 14 was found to be
the most active one with an IC50 value of 0.19 lM. On the
basis of their results a good aromatase inhibitor can be
achieved with the structures including a framework of
diarylalkyl moiety containing a lengthened C chain linked
to the 1- or 4(5)-positions of imidazole. An especially
favorable framework seems to be a,x-diarylalkyl with 3 or
4 carbon atoms in the bridge, which connects the frame-
work to the heterocycle. The best substituents as per the
aromatase activity are the cyano group in the a-phenyl ring
and fluorine atom in x-phenyl ring.
N
NH
F N
N
14
Vascular endothelial growth factors (VEGFs) and their
respective family of receptor tyrosine kinase (VEGFRs) are
key proteins modulating angiogenesis, the formation of new
vasculature from an existing vascular network. Potent, spe-
cific, and non-toxic inhibitors of angiogenesis are powerful
clinical tools in oncology acting by signal blockade of
VEGF receptors, including both VEGFR-1 and VEGFR-2.
In view of above, Kiselyov et al. (2006) synthesized novel
potent derivatives of hetaryl imidazoles and evaluated for
their inhibitory activity against VEGF receptor II (VEGFR-
II). Among the synthesized compounds several displayed
good VEGFR-II inhibitory activity, specially compound
15, i.e., (3,4-dimethoxy-phenyl)-(5-{3-methyl-5-[(pyridin-4-
ylmethyl)-amino]-3H-imidazol-4-yl}-[1,3,4]oxadia-zol-2-yl)-
amine was found to be most potent one.
H
O N
N tosterone biosynthesis in rats and reduction in the weight of
N
N achieved with the hydroxyl group derivative 1-(6,7-dime-
OCH3
N
N
H OCH3
N selective inhibitor. Compound 17 showed a potent sup-
15
Platelet-derived growth factor receptors (PDGFRs)
have been implicated in a number of pathologies, espe-
cially in various cancers and are therefore considered as
promising drug targets. A series of N-(3-(4-(pyridine-3-
yl)-1H-imidazol-2-ylamino) phenyl)amides were synthe-
sized and tested for their inhibition of PDGFR. The novel
4-methyl-N-(4-methyl-3-(4-(pyridin-3-yl)-1H-imidazol-2-
ylamino)-phenyl)benzimidazole 16 obtained by replace-
ment of the pyrimidine system in Imatinib (well known
and highly selective tyrosine kinase inhibitor) with an
imidazole ring, exhibited potent inhibitory activity in
PDGFR, similar to the parent compound (Mahbootri
et al., 2008).
H
N N N
HN N
16
C17,20-lyase is one of the key enzyme responsible for the
biosynthesis of androgens that catalyzes the conversion of
17 a-hydroxypregnenolone and 17 a-hydroxyprogesterone
into the weak androgens, dehydroepiandrosterone, and
androstenedione, respectively, in testes and adrenal glands.
Since these weak androgens are subsequently converted
into more potent androgens such as testosterone and
dihydrotestosterone in prostate cancer cells, the inhibition
of C17,20-lyase could prevent initial androgen production
and consequently prevent subsequent conversion to more
potent androgen. A series of 1- and 4-(2-naphthylmethyl)-
1H-imidazoles have been synthesized and tested for their
enzyme inhibitory activities, suppressive effects on tes-
prostate and seminal vesicles in rats. The best results were
thoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methylpropan-
1-ol 17, which was effective in expressing pharmacological
activities and removing the effect of liver weight. Through
the examination of selectivity for C17,20-lyase over 11b-
hydroxylase 17 was found to be more than 260-fold
pression of testosterone biosynthesis after a single oral
administration in monkeys (Matsunagu et al., 2004).
 Med Chem Res

OH Cl
Cl

N
N
N
NH O

17 NC N

The past decade has seen a growing interest in farnesyl 19

protein transferase (FPT), an enzyme which catalyzes a key
step in the anchoring of Ras protein to the cell membrane.
Once attached to the cell membrane Ras is acting as a
signal transducer from external growth factors to the cell
nucleus. Mutated forms of Ras are found in approximate
30% of human cancers providing a continuous signal for
the transformation and uncontrolled growth of malignant
tumor cells. Therefore, it was hypothesized that inhibitors
of FPTs would be important for the development of novel
cancer therapeutic drugs (Angibaud et al., 2003).
Lin et al. (2004) synthesized a novel class of 1-benzyl-
5-(3-biphenyl-2-yl-propyl)-1H-imidazole analogues as
anti-cancer agents and tested them in vitro for their farnesyl
transferase inhibitory activity. Compound 18, 40 -tert-butyl-
A series of imidazole-containing methyl ethers have
been designed and synthesized as potent and selective
farnesyl transferase inhibitors (FTIs) by transposition of the
D-ring to methyl group on the imidazole of previously
reported FTIs. Compounds 6-[3-(4-cyano-benzyl)-3H-imi-
dazol-4-yl-methoxymethyl]-40 -trifluoromethyl-biphenyl-3-
carbonitrile 20 and 6-[3-(4-cyano-benzyl)-3H-imidazol-4-
yl methoxymethyl]-30 -napthyl-biphenyl-3-carbonitrile 21
demonstrated superior enzymatic activity to the current
benchmark compound tipifarnib with EC50 values of 1.6
and 1.2 nM, respectively (Li et al., 2004a, b).
CF3
NC

6-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethoxymethyl]
biphenyl-3-carbonitrile has been identified as most potent
enzyme inhibitor.

CN O
N
N
O NC
N 20
NC

CN

N
N
18 O

As a part of their efforts to identify potent inhibitors of NC

farnesyl transferase (FTase), Li et al. (2004a, b) modified
the structure of farnib through structure-based design by
replacing the 2-quinolones with 4-quinolones and pyri-
dones, and subsequent relocation of the D-ring to N-methyl
group on the imidazole ring. From the study, 1-(3-chloro-
phenyl)-7-[1-(4-chlorophenyl)-1-(3-methyl-3H-imidazol-4-yl)
ethyl]-4-oxo-1,2,3,4-tetrahydro-quinoline-3-carbonitrile 19
emerged as potent and selective FTase inhibitor.
21
Imidazoles as enzyme inhibitors
Imidazoles as b-lactamase inhibitors
b-Lactamases are serine and metallo-dependent enzymes
produced by the bacteria in defense against all classes of
Med Chem Res
b-lactam antibiotics, such as penicillins, cephalosporins,
carbapenems, and monobactams. In order to overcome this
resistance, several b-lactamase inhibitors such as clavulinic
acid, sulbactam, and tazobactam are widely used in the clinics
in combination with the b-lactam antibiotics. However, single
point mutations within these enzymes have allowed bacteria
to overcome the inhibitory effect of commercially approved
b-lactamase inhibitors. Although the commercially available
b-lactamase inhibitor/b-lactam antibiotic combinations are
effective against class-A-producing bacteria and many
extended spectrum b-lactam antibiotic combinations are less
effective against class-C enzymes expressing bacteria. To
circumvent this problem, Venkatesan et al. (2004) synthe-
sized several novel imidazole substituted 6-methylidene-pe-
nem derivatives and tested them in vitro against TEM-1 and
AmpC enzymes for their inhibitory activity. (5R),(6Z)-
6-(2-benzyl-1H-imidazol-4-ylmethylene)-7-oxo-4-thia-1-aza-
bicycle-[3.2.0]-hept-2-ene carboxylic acid sodium salt 22,
when combined with piperacillin, rendered 90% of the tested
organism susceptible.
ONa
S
O NH
N N
HN
O N
22
In continuation of their study, they further synthesized
several novel 5,5,6-fused tricycles bearing imidazole and
pyrazole 6-methylidene penems. Among the synthesized
compounds (5R),6(Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo
[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicy-
clo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt 23 was
found to be an active broad spectrum inhibitor of b-lacta-
mases (Venkatesan et al., 2008).
N
S a major metabolite of arachidonic acid produced in kidney.
N
S
N by cytochrome P450 (CYP) 4A isoenzymes (CYP4A1,
O
COONa
23
Imidazoles as carbonic anhydrase activators
Carbonic anhydrase (CA) deficiency syndrome is a genetic
disease of bone, brain, and kidney affecting a large number
of people. In this condition, a certain CA isoenzyme gene is
either not expressed, or its protein product is unstable due
to deleterious mutation and the corresponding CA isoen-
zyme is absent in blood, kidney, or lung of such people. No
pharmacologically specific treatment for this condition is
available as yet, although the possibility of activating
certain CA isoenzymes has been investigated thoroughly in
the last few years.
In continuation of this, Scozzafava and Supuran (2000)
synthesized imidazole-based compounds with general for-
mula Cpu-AA-Hst (cup, 4-ClC6H4SO4NHCO). An ex vivo
CA activation test on normal blood red cells (containing
150-lM HCA I and 20-lM HCA II) showed that histamine
has produced only a weak activation of around 130% of
basal CA activity after 1 h incubation where as among the
synthesized compounds, 4[b-(4-chlorophenylsulphonylur-
eido-b-alanyl-histidylamido)ethyl]-1H-imidazole 24 pro-
duced 190 ± 6% CA activity after 30 min of incubation
and 245 ± 8% after 1 h which is more than histamine.
Thus, compound 24 can be used in the treatment of genetic
diseases of bone, brain, and kidney.
Cl
N
O
S O
O
N NH2
NH
HN
HN
O
O
H2N
24
Imidazoles as 20-HETE synthase inhibitors
20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is
The formation of 20-HETE from amino acid is catalyzed
4A2, 4A3, and 4A8) in rat kidney and cerebral artery, and
by CYP4A11 and 4F2 in human liver and kidney. 20-
HETE plays an important role in the regulation of renal
vascular tone in the cerebral circulation. Therefore, the
inhibition of 20-HETE is now considered as promising new
target treatment of renal and cerebrovascular diseases. In
continuation of their efforts in search of 20-HETE inhibi-
tors, Nakamura et al. (2004) synthesized imidazole-based
compounds and found that [6-(4-imidazol-1-yl-phenoxy)-
hexyl]dimethyl amine 25 exhibited strong inhibitory
 Med Chem Res

activity against 20-HETE synthase with an IC50 value of
8.8 nM and more than 180-fold to over 15,000-fold
selectivity toward CYP1A2, 2C9, 2C19, 2D6, and 3A4.
N
enzymes. In view of above, Roman et al. (2007) synthe-
sized a series of 2-oxy-substituted-1-(1H-imidazol-1-yl)-4-
phenylbutanes as heme oxygenase inhibitors and found
4-(4-fluoro-phenyl)-1-imidazol-1-yl-butan-2-one 27 was
the effective one among the synthesized compounds.

N N
O
H3 C

N N

H3C O

F
25
27
Imidazoles as carboxypeptidase A inhibitors
Imidazoles in treatment of CVS disorders
Carboxypeptidase A (CPA) is one of the most studied zinc-
Imidazoles as anti-coagulants
containing proteolytic enzymes and serves as a prototypical
enzyme for metalloproteases that play important roles in
Thrombin-activatable fibrinolysis inhibitor (TAFI) was
biological system. In view of above, Han and Kim (2001)
recently identified as an inhibitor of fibrinolysis. TAFIa is a
synthesized competitive inhibitors of carboxypeptidase A,
zinc-containing carboxy peptidase that removes basic
2-(4-imidazolyl) hydrocinnamic acid and its congeners that
C-terminal arginine and lysine residues from peptides and
bear an imidazole ring as zinc-ligating functionality been
proteins, such as those present on partially degraded fibrin
evaluated for their CPA inhibitory activity. From the study,
clots. The presence of these residues on fibrin accelerates
it was reported that compound 2-benzyl-3-(1H-imidazol-4-
plasmin generation, and therefore fibrinolysis, by serving
yl)propionic acid 26 may potentially be explored as
as an anchor for the formation of the plasminogen/t-PA
therapeutic agent that can selectively control rapidly pro-
complex. As a result TAFIa serves as a clot stabilizer and
liferating breast cancerous cells.
its inhibition should therefore stimulate endogenous fibri-
nolysis and thereby exert an anti-thrombotic effect. In view
of above, Nantermet et al. (2004) synthesized imidazole
H acetic acid TAFIa inhibitors and found that 3-(3-amino-
N
cyclopentyl)-2-[1-(3,3-dimethyl-butyl)-1H-imidazol-4-yl]
OH
propionic acid 28 was most active one.
N
COOH
O
N
NH2

26
N

Imidazoles as heme oxygenase inhibitors

Heme oxygenases (HOs), comprising two active isozymes
HO-1 (inducible) and HO-2 (constitutive), are enzymes
responsible for heme degradation in vivo, a process which
generates carbon monoxide (CO) whose cellular regulatory
actions have been recently acknowledged. Inhibitors of
theses enzymes may prove indispensable pharmacological
tools for the investigation of the CO/HO system and related
physiological pathways. Furthermore, investigation of
mechanism of protective effect in acute renal failure, its
beneficial involvement in cardiovascular system injuries, or
its central role in neurogenerative disorders significantly
depends on the availability of the inhibitors of these
28
Imidazoles as NOs inhibitors
The reperfusion of ischemic tissue often delays the physio-
logical and functional recovery. This paradoxical effect is
ascribed to increased release of free radicals including O2-
and NO. For these reasons, scavenging reactive oxygen
species or inhibition of the NO synthesis has been shown to
result in an enhanced neuronal survival after cerebral
ischemia. In view of above, Sorrenti et al. (2006) synthesized
a novel series of imidazole derivatives and evaluated them
for their NOS inhibitory activity. Among the synthesized
Med Chem Res
compounds, 2-(2-methyl-imidazol-1-yl)-1-(4-nitrophenyl)-
ethanone 29 showed an inhibition of 32% for iNOS at
500 lM dose.
N N
NO2
N
O
29
Imidazoles as modulators of calcium-activated potassium
channel
The large conductance calcium-activated potassium chan-
nel (BK) is a ubiquitously expressed potassium channel
that has been implicated in a variety of physiological
processes. The channels are activated both by depolariza-
tion and by elevated calcium levels. In smooth muscle, they
have been shown to maintain myogenic tone by shortening
the action potential. Furthermore, BK channels have been
implicated in the regulation of neurotransmitter release.
Given its importance in maintaining myogenic tone, acti-
vation of the BK channel presents a possible mechanism
for the treatment of asthma or hypertension. Thus, Power
et al. (2006) synthesized a series of partial structures of
ketoconazole and tested for their activity on the large
conductance calcium-activated potassium channel (BK) in
bovine smooth muscle cells. The results indicate that 1-(4-
{2-[(2,4-dichlorophenyl)imidazol-1-yl-methyl][1,3]-dioxo-
lan-4-ylmethoxy}phenyl)piperidine 30 has emerged as best
blocker with % inhibition of 95 ± 35 at concentration of
30 lM and 1-(4-{2-[(2,4-dichlorophenyl)imidazol-1-yl-
methyl][1,3]dioxolan-4-yl methoxy}phenyl)piperazine 31
as best opener with % opening of 566 ± 200 at 30 lM.
Cl
N Cl
O O
O
Br
30
Cl
Cl
O O NH2
N
31
Imidazoles as anti-inflammatory agents
p38 MAP kinase inhibitors
Rheumatoid arthritis is a chronic debilitating disease. Tumor
necrosis factor (TNF-a) and interleukin (IL)-1b are proin-
flammatory cytokines implicated as casual agents in the onset
and progression of the bone and joint destruction which
characterizes chronic rheumatoid arthritis. The release of and
response to TNFa and IL-1b are regulated by a mytogen-
activated protein (MAP) kinase known as p38. In view of
above, Mclay et al. (2001) synthesized 2-(2-dioxanyl) imid-
azole (RPR132331) and found it to be an inhibitor of TNFa
release from lipopolysaccharide (LPS)-stimulated human
monocytes. An intensive programme of work exploring the
biology, toxicity, and physical chemistry of a novel series of
inhibitors, derived from RPR132331, has led to identification
of RPR200765A, a development candidate for the rheumatoid
arthritis. 2-[5-(4-fluoro-phenyl)-4-pyridin-4-yl-1H-imidazol-
2-yl]-5-methyl-[1,3]dioxan-5-yl}morpholin-4-yl-methanone
(RPR200765A, 32) was found to be a potent and selective
inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibited
LPS-stimulated TNFV release both in vitro from human
monocytes (EC50 = 110 nM) and in vivo in Bal b/c mice
(ED50 = 6 mg/kg).
N
O
O
N
N
NH O
O
F
32
Adams et al. (2001) synthesized a series of N-1-cyclo-
alkyl-4-aryl-5-(pyrimidin-4-yl)imidazole derivatives and
screened them for their p38V MAP kinase inhibitory
activity. Among the synthesized compounds, 2-methoxy
 Med Chem Res

pyrimidine compounds, 4-[5-(4-fluoro-phenyl)-3-piperidin- 5-LOX inhibitors

4-yl-3H-imidazole-4-yl]-2-methoxy-pyrimidine 33 and 4-
[4-(4-fluoro-phenyl)-5-(2-methoxy-pyrimidin-4-yl)imidazol- Leukotrienes (LTs) have been implicated in a number of
1-yl]cyclo hexanol 34 were found to be active ones and human disease states including asthma, rheumatoid arthri-
these reduced inhibition of CRaf and JNK1 which is an tis, inflammatory bowel diseases, and psoriasis. Accord-
additional advantage. ingly, any agent that controls the release or actions of the
LTs is expected to be of considerable therapeutic value for
NH
the treatment of acute and chronic inflammatory conditions.
N With an aim to improve oral absorption, Mano et al. (2003)
incorporated ionizable group into the known 5-lipooxygenase
H3CO
N N (5-LOX) inhibitor ZD 2138 36 and synthesized a novel series
of imidazole compounds. From the series, 4-[5-fluoro-3-[4-
N
(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-4-methoxy-
3,4,5,6-tetrahydro-2H-pyran hydrochloride salt 37 was
discovered as an orally active 5-LO inhibitor, selective over
12-LO and cyclooxygenase and it was found to be more
F soluble in the physiologic pH range than ZD2138. Compared
to ZD2138, compound 37 elicited comparable inhibitory
33
potency in the in vitro HWB assay, and demonstrated
OH
improved activity in the in vivo rat foot edema test and
superior pharmacokinetic parameters (bioavailability, Cmax)
N in monkeys.
H3CO F
N N

N OCH3

O
O N
F
CH3
34
36
A series of imidazolyl benzimidazoles and imidazo[4,5-
b] pyridines was synthesized and screened for their p38a F

MAP kinase inhibitory activity. All the synthesized com- N

pounds were evaluated in a 14-day chronic model of N O
inflammation, the rat collagen-induced arthritis (CIA) and
activity was assembled by effect on paw swelling and by
histopathology scores. In the mouse model, imidazopyri- O
dine derivative compound 5-[2-(2,6-dichloro-phenyl)-5-
O
phenyl-3H-imidazol-4-yl]-1-isobutyl-1H-imidazo [4,5-b]
pyridin-2-yl amine 35 showed improved potency when
compared to the benzimidazoles (Mader et al., 2008). 37

H Cl TRPV-1 antagonists
N
N Vanilloid receptor-1 (VR1 or TRPV1) is a member of the
H2N N N
transient receptor potential (TRP) family of ion channels.
N This highly Ca2? permeable receptor is predominantly
Cl
expressed in peripheral sensory neurons that are involved
in nociception and neurogenic inflammation. Gore et al.
(2007) synthesized a novel series of 4,5-biarylimidazoles
as TRPV-1 antagonists and the analogs were evaluated for
35 their ability to block capsaicin- or acid-induced calcium
Med Chem Res
influx in TRPV-1-expressing CHO cells. These studies led
to the identification of a highly potent and orally bio-
available TRPV1 antagonist 38.
F F
F 50 mg/kg po, respectively (Sondhi et al., 2005).
N N
N N
CF3
HO N N
H
Cl
38
COX-2 inhibitors
The differential tissue distribution of COX-1 (cyclooxy-
genase-1) and COX-2 (cyclooxygenase-2) provides a
rationale for the development of selective COX-2 inhibi-
tors as anti-inflammatory analgesic agents that lack the side
effects exhibited by traditional non steroidal anti-inflam-
matory drugs (NSAIDs). However, emerging evidence
suggests that adverse reactions such as GI irritations or
ulceration and renal liabilities are associated with pro-
longed use of COX-2 selective inhibitors. Thus, there is a
need for the design of COX-2 inhibitors with a greater
safety profile for the treatment of arthritis. Keeping this in
mind, Navidpone et al. (2007) synthesized a new type of
1-aryl-5-(4-methylsulfonylphenyl) imidazoles possessing
C-2 alkylthio (SMe or SEt) substituents and evaluated for
their selective COX-2 inhibitory activity. The compound
1-(4-bromophenyl)-5-(4-methylsulfonylphenyl)-2-methyl-
thioimidazole 39 was found to be most potent and selective
COX-2 inhibitor (COX-2 IC50 = 0.43 lM with no inhibi-
tion of COX-1 up to 25 lM) relative to the reference drug
celecoxib (COX-2 IC50 = 0.21 lM with no inhibition of
COX-1 up to 25 lM) and also showed very good anti-
inflammatory activity in carrageenan-induced rat paw
edema assay.
Br
O
S
O
N
S Among the synthesized derivatives 5-(3-benzyloxyphenyl)-4-
N (3-chlorophenyl)-2-(4-piperidyl) imidazole dihydrochloride
39
Various monocyclic, bicyclic, and tricyclic pyrimidine
derivatives have been synthesized and evaluated for their anti-
inflammatory and analgesic activities. Among the synthesized
compounds 7-methyl-5-thioxo-1,5,6,7,8,8a-hexahydro-imi-
dazo[1,2-c]pyrimidine-2,3-dicarbonitrile 40 exhibited good
analgesic and anti-inflammatory activity, i.e., 70 and 34.3% at
S
NC
NH
NC
N
H
40
Imidazoles as anti-infectious agents
Imidazoles as anti-bacterial agents
As pathogenic microorganisms continuously evolve mech-
anisms of resistance to currently used anti-microbial agents,
the discovery of novel and potent bactericides is the best
way to overcome bacterial resistance and develop effective
therapies. Khabnadideh et al. (2003) carried out N-alkylation
of imidazole, 2-methylimidazole, and 2-methyl-4-nitroimi-
dazole to achieve effective anti-bacterial agents. The syn-
thesized compounds were then investigated for their
anti-bacterial activity against Escherichia coli, Staphylo-
coccus aureus, and Pseudomonas aeruginosa. Among the
synthesized compounds, 1-nonylimidazole 41 was found to
be the most active one with minimum inhibitory concen-
tration (MIC) 10, 39, and 19 lg/ml and minimum bacteri-
cidal concentration (MBC) values of 19, 78, and 39 lg/ml
against S. aureus, P. aeruginosa, and E. coli, respectively.
N
N
41
Tanitame et al. (2004) synthesized imidazole derivatives of
1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyr-
azole and screened them for their anti-bacterial activity.
42 showed anti-bacterial activity at 2 lg/ml concentration
against FDA 209P and KMP9 strains of S. aureus.
 Med Chem Res

HO

O H
N HO
N
NH
COOH
N H

N
Cl HO
H
NHCOCH3
Cl Cl

45
42

Copper complexes of thiosemicarbazones of imidazole-

2-carbaldehyde 43, pyrrole-2-carbaldehyde and indole-
3-carbaldehyde were synthesized and evaluated for their
anti-fungal and anti-bacterial activities against a variety O O
N HO
of microorganisms. The copper complex of imidazole-2-
carbaldehyde thiosemicarbazone was found to be active
against fungi (Rodrignez-argulles et al., 2005). N

R O O
S N

H2N N N
H N
H
46
43

A series of chloroaryloxyalkyl imidazole and benz-
imidazole derivatives were synthesized and evaluated in
vitro against Salmonella typhi O-901 and S. aureus A
15091. Among the compounds synthesized, 1-[4-(4-chlo-
rophenoxy)butyl]-1H-imidazole 44 showed significant
activity against S. typhi O-901 with MIC value of 8.5 lg/
ml (Khalafi-Nezhad et al., 2005).
Cl
Cl
N 1.563, 0.391, and 0.781 lg/ml, respectively (Bhandari
N
O
A series of novel (Z)- and (E)-2-imidazolo-/triazolo-
methyl tetrahydronaphthyl oxime ethers were synthesized
as conformationally constrained analogues of oxiconazole
and evaluated for their anti-fungal and anti-bacterial
activities. Most of these derivatives exhibited potent anti-
bacterial activity and surprisingly none of them was active
against fungal strains. However, (Z)-5-bromo-2-imidazol-
1-ylmethyl-3,4-dihydro-2H naphthalen-1-one O-(3-chloro-
benzyl)-oxime 47 was found to be most active one against
K. pneumonia, E. coli, and S. aureus with MIC value of
et al., 2009).

44
N

Sugar-annulated imidazoles have received particular

interest recently due to the remarkable capacity of naturally N

occurring Nagstatin 45 to inhibit glucosaminidases. In view

of above, Nagarapu et al. (2008) synthesized a series of
novel C-linked imidazole glycoconjugates and evaluated
O Br
their anti-bacterial activity. Among the synthesized com- Cl N
pounds, the compound 46 showed moderate anti-bacterial
activity against Gram positive (Bacillus subtilis, S. aureus,
and Staphylococcus epidermidis) and Gram negative
(E. coli, P. aeroginosa, and Klebsiella pneumoniae) bacteria. 47
Med Chem Res

Imidazoles as anti-fungal agents Malassezia-associated skin diseases, including tinea ver-

sicolor, folliculitis, and seborrheic dermatitis, is one of the
Recently, there has been a renewed interest in anti-fungal major classes of superficial cutaneous mycotic infections
drug research and development. The currently available caused by several different Malassezia spp. and is usually
therapy suffers from drug related toxicity, hazardous drug– subjected to topical anti-fungal treatment. Therefore, an anti-
drug interactions, less satisfactory pharmacokinetics, and fungal agent of topical use should have good activity against
development of resistance. Imidazole drugs such as mico- such Malassezia spp. This stimulated Uchida et al. (2003) to
nazole, econazole, and ketoconazole have been used to synthesize novel imidazole anti-fungal agent NND-502 50,
treat fungal diseases because of their low toxicity and wide to test it against major three Malassezia spp. viz. M. furfur,
anti-microbial spectrum that includes yeasts, mycelial M. sympodialis, and M. slooffiae. The results suggested that
fungi, and Gram positive bacteria. This created interest in NND-502 might be beneficial in treatment of Malassezia-
researchers to develop a new anti-fungal agent based on associated skin diseases.
imidazole nucleus. Herein, we have summarized some of
the reported work on imidazoles as anti-fungal agents.
Saha et al. (2000a, b) synthesized novel 4-substituted Cl Cl
imidazole derivatives and screened them for their
anti-fungal activity. Among the synthesized compounds,
S CN
40 -fluoro-biphenyl-4-sulfonic acid (2,4-dimethyl-pent-3-
enyl)-(1H-imidazol-4-ylmethyl)-amide 48 showed good
N
activity against Mucosporum canis, Crytococcus neofor- S
mans, and Aspergillus fumigatus.
A series of 4-substituted imidazole sulfonamides had been N
prepared by solid phase chemistry. These compounds were
found to have good in vitro anti-fungal activity and constitute 50
the first example of C-linked azoles with such activity. The
most potent inhibitor 4-butoxy-N-(1-cyclohexyl-propyl)-
N-(3H-imidazol-4-ylmethyl)-benzenesulfonamide 49 dem-
A series of (Z)-trans-3-azolyl-2-methylchromanone
onstrated inhibition of key Candida strains at an in vitro
oxime ethers were stereoselectively synthesized and tested
concentration of less than 100 nM (Saha et al., 2000b).
for their in vitro anti-fungal activity. Many of these
derivatives exhibited high activity against Candida albi-
cans, Saccharomyces cerevisiae, A. niger, and M. gypse-
F um. Among the synthesized compounds, [4-(2,4-dichloro-
phenyl)-[1,3]dithiolan-2-ylidene]imidazol-1-yl-acetonitrile
51 exerted significant in vitro anti-fungal activity more
HN potent than the reference drugs oxiconazole and fluconaz-
N ole (Emami et al., 2004).
N S
O2

48

O
N
N

N
O2
S

N
C2H5 O
Cl O

51

N NH
Emami et al. (2008) synthesized 2-hydroxyphenacyl
azoles and 2-hydroxyphenacyl azolium derivatives and
49 evaluated their anti-fungal activity against C. albicans,
 Med Chem Res

S. cerevisiae, A. niger, and M. gypseum. Among the syn- HN

H
N
O

thesized compounds, 1-(2-hydroxy-4-methoxyphenyl)-2- C2 H5

N
imidazol-1-yl-ethanone 52 was found to be most active one
N
having activity more than reference drug fluconazole.
N

O O

N
OH O
OH
HO
N
OH

54
H3CO

52 Different analogues of capravirine (AG-1549) 55 were

Imidazoles as anti-viral agents
With over one million child deaths per year, measles virus
(MV) is a major human pathogen, and ranks 8th as the
cause of death worldwide, especially in the developing
countries. Despite large vaccination campaigns, MV is still
resisting eradication, and there is no available therapeutic
treatment. The synthesis and in vitro anti-measles virus
(anti-MV) activity of a class of ring-expanded (‘‘fat’’)
nucleoside analogues containing the heterocyclic ring
system are reported. The target compounds were synthe-
prepared and tested for activity against HIV-1 in MT-4
cell cultures infected with wild-type HIV-1 (strain IIIB).
Among the synthesized compounds, 2-[1-(benzyloxym-
ethyl)-5-(3,5-dimethylbenzyl)-4-isopropyl-1H-imidazol-2-
ylthio] acetamide 56 showed the most potent activity
(IC50 = 0.15 lM), but was lower than the uracil reference
compound Emivirine (IC50 = 0.03 lM) (Loksha et al.,
2005).
O
H2N O
N

sized by base-catalyzed condensations of 4,5-dicarboxylic H2C

acid esters of the appropriately substituted imidazole-1-ri- N
bosides with suitably substituted guanidine derivatives. S

Compounds were screened for their anti-MV activity in N

African green monkey kidney cells (CV-1), employing

ribavirin as the control standard. While the parent com-
pound itself failed to show any significant anti-viral Cl
Cl
activity against MV, its analogues containing hydrophobic
substituents at the 2-position 53 or the 6-position 54
showed promising anti-viral activity at submicromolar or 55
micromolar concentration levels with no apparent toxicity
to the host cell line. Both the compounds showed higher H2N

anti-MV activity than the control drug ribavirin (Zhang N

et al., 2002). O S

N
H O
H2N N O

N
N

O O
56

OH
HO 4-Carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-
OH 2-yl)imidazole-1-b-D-ribofuranoside 57 was synthesized
by the reaction of ethyl 1-(2,3,5-tri-O-benzoyl-b-D-ribo-
53 furanosyl)-5-formylimidazole-4-carboxylate with excess
Med Chem Res

guanidine in ethanol at reflux, and evaluated in vitro
against NTPases/helicases of four different viruses of the
Flaviviridae family, including the West Nile virus (WNV),
hepatitis C virus (HCV), dengue virus (DENV), and the
Japanese encephalitis virus (JEV), employing both an RNA
and a DNA substrate and found to be highly active against
WNV with IC50 value of 23 lM (Ujjinamatada et al.,
2007).
A series of new bis-imidazole derivatives have been
synthesized and tested for their anti-fungal activity against
C. albicans 3038 and C. glabrata 123 as well as anti-
mycobacterial activity against M. tuberculosis H37Rv reference
strain. Among the synthesized compounds, 1-(4-biphenylyl)-
3-(1H-imidazol-1-yl)-2-[(1H-imidazol-1-yl)methyl]-1-pro-
pan-1-one 59 was found to be active against all the tested
strains in range of 2-8 lg/ml (Zampieri et al., 2007).

O
H2N

O
N N
NH2
N
N

N NH N
N
O

NH2 N

HO
OH

HO 59

57 1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidaz-
ole derivatives were synthesized and tested for their in vitro
anti-fungal activity against C. albicans as well anti-
Imidazoles as anti-tubercular agents mycobacterial activity against M. tuberculosis H37Rv ref-
erence strain. Among the compounds synthesized, (±)
Tuberculosis is a devastating worldwide problem, whose trans-(4,5-dihydro-1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-
control is complicated by a number of confounding factors imidazole 60 was found to be active against both C. albi-
including development of multi-drug-resistant (MDR) cans (IC50 = 1 lg/ml) and M. tuberculosis H37Rv
strains to commonly used drugs, substantially long course (IC50 = 8 lg/ml) (Zampieri et al., 2008).
of therapy, and lack of affordable cheap drugs in the cases
involving patients suffering due to MDR tuberculosis. In
view of above, Gupta et al. (2004) synthesized a series of
ring-substituted-1H-imidazole-4-carboxylic acid deriva-
tives, and 3-(2-alkyl-1H-imidazol-4-yl)-propionic acid
derivatives, and screened them for their anti-tubercular
N N
potential against drug-sensitive and drug-resistant
Mycobacterium tuberculosis H37Rv strains. Among the N
synthesized compounds the most effective analogue 2,5- HN
dicyclohexyl-1H-4-imidazole carboxylic acid ethyl ester 58
exhibited 99% inhibition at a concentration of 6.25 lg/ml.

60
O
O
Imidazoles as Leishmanicidal agents

Leishmaniasis is caused by several species of protozoan

N parasites transmitted by the bite of female phlebotomine
NH sand fly. This disease is currently prevalent in four countries,
being endemic in 88 countries threatening 350 million peo-
ple worldwide. Classified as an extremely neglected disease,
58 leishmaniasis is still present as an additional difficulty in the
 Med Chem Res

long and inefficient treatment that is dependent on old and

highly toxic drugs. A series of 2-(1-methyl-5-nitroimidazol-
2-yl)-5-(1-piperazinyl, 1-piperidinyl and 1-morpholinyl)-
1,3,4-thiadiazoles were synthesized and evaluated for their
N
in vitro leishmanicidal activity against Leishmania major O
promastigotes. The results revealed that compound 1-[5-(1-
methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-yl] N
H
piperazine 61 was the most active compound with an IC50
value of 0.19 lM (Foroumadi et al., 2005).
63

O
NH Imidazoles as anti-malarial agents
- N+
O
N N
S Malaria is one of the most deadly diseases for humans
worldwide and more than 2.5 million people die from it
N N each year. There is a need of synthesizing new chemical
N
moiety having potential anti-malarial activity because of
61 the emergence and ongoing spread of the chloroquine-
resistant strains of Plasmodium falciparum, including
multi-drug resistant strains to conventional anti-malarial
In order to find new drugs with anti-leishmanial activity,
drugs. In view of above, Kawanishi et al. (2004) synthe-
Ferreira et al. (2007) synthesized and evaluated new
sized a series of 3-methoxy-1,2-dioxane derivatives and
imidazole and triazole compounds carrying either the
evaluated them for their in vitro as well in vivo anti-
carbaldehyde or the difluoromethylene functionalities
malarial activity. Among the synthesized compounds,
against promastigote forms of L. amazonesis. Among the
imidazole analogue N-[2-(1H-imidazol-4-yl)ethyl]-2-(3-
compounds tested, 1-(4-chlorophenyl)-5-(difluromethyl)-2-
methoxy-3-pentyl-1,2-dioxan-6-yl) acetamide 64 showed
methyl-1H-imidazole 62 has significantly reduced the
desirable in vivo anti-malarial activity against P. berghci
number of viable L. amazonesis promastigote forms. The
infected mice.
results showed that the introduction of the difluorometh-
ylene moieties has turned the inactive carbaldehyde into
active anti-leishmanial compounds.
HN
N

F
O

HN O O
N Cl
N

62 64

Imidazoles as trypanocidal agents Vlahakis et al. (2006) synthesized a series of imidazole-

Moura et al. (2004) synthesized new naphthoimidazoles
form b-lapachone with an aromatic moiety linked to the
imidazole ring using phenylic and heterocyclic aldehydes.
4,5-dihydro-6,6-dimethyl-6H-2-(40 -methyl phenyl)-pyr-
an[b-4,3]naphtha[1,2-d]imidazole 63 was found to be most
active compound against Trypanosoma cruzi with an EC50
value of 15.5 ± 2.9 lM.
dioxalone compounds and assayed for their inhibitory
activity in P. falciparum cultures and the results were
compared to those obtained with Chinese hamster ovary
(CHO) cells. Among the synthesized compounds, 4-{2-[2-
(4-chloro-phenyl)-ethyl]-2-imidazol-1-ylmethyl-[1,3]diox-
olan-4-ylmethylsulfanyl}-phenol 65 displayed both high
potency in P. falciparum cultures and low CHO cell
inhibitory activity.
Med Chem Res
S
OH
O N
O
N
N
Cl
65
Imidazoles in treatment of metabolic disorders
Imidazoles as anti-diabetic agents
A number of imidazoline-containing compounds have
been reported to induce insulin release from isolated
pancreatic islets and more importantly to improve glucose
tolerance in both rats and mice. The putative imidazoline
receptor site responsible, present on the pancreatic b-cells,
has been termed the atypical imidazoline or I3 site since it
shows pharmacological properties which distinguish it
from the previously identified I1 and I2 sites found in other
tissues. In view of above, Mayer and Taberner (2002)
studied the I3 receptor antagonistic activity of 2-(2-ethyl-
2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) 66
on blood glucose level in vivo, and suggested that these
drugs may act at sites other than I3 receptor to reduce
blood glucose.
O N
HN
66
AMP-activated protein kinase (AMPK) is an important
signaling effector that couples cellular metabolism and
function. The effects of AMPK activation on pancreatic
b-cell function remain unresolved. In view of above, Wang
et al. (2005) used 5-amino-imidazole carboxamide riboside
(AICAR) 67, an activator of AMPK, to define the signaling
mechanisms linking the activation of AMPK with insulin
secretion. From the study they come to a conclusion that
AICAR stimulated insulin secretion by both KATP chan-
nel-dependent and -independent pathways.
O
NH2
HN
H2N
O OH
HO OH
OH
67
Imidazoline derivatives have been reported to show anti-
hyperglycemic activity in vivo. In view of above, Crane
et al. (2006) designed and synthesized novel imidazoline
derivatives and screened them for their potent anti-hyper-
glycemic activity in type-2 diabetes rat model. Among the
synthesized compounds, 2-(a-cyclohexyl-benzyl)-4,5-
dihydro-1H-imidazole 68 exhibited potent anti-hypergly-
cemic property having pKi values of 7.23 and 7.38 against
imidazoline preferring binding sites I1 and I2, respectively.
HN
N
68
Imidazoles as anti-obesity agents
Excess energy intake leading to obesity has emerged as a
major health threat in industrialized nations, increasing the
chances for obese individuals of developing type-2 diabe-
tes, hypertension, heart disease, stroke, cancer, and arthri-
tis. The cannabinoid receptor Type 1 (CB1) and its
endogenous ligands, the endocannabinoids, have been
found to be involved in the control of weight and energy
balance via a dual mechanism of food intake modification
and the regulation of energy expenditure. Keeping this in
mind, Plummer et al. (2005) synthesized a series of
4,5-diarylimidazole-2-carboxamide analogs, and evaluated
 Med Chem Res

them for their human CB1 receptor inverse agonistic
activity. Among the synthesized compounds, 5-(4-chloro-
phenyl)-4-(2,4-dichloro-phenyl)-1-methyl-1H-imidazole-
2-carboxylic acid cyclohexylamide 69 demonstrated
reduction in both food intake and overall body weight.
Cl CH3
O
N
Volke et al. (2003) studied the inhibition of NO synthesis by
selective NOS inhibitor 1-(2-trifluoromethyl phenyl)imidaz-
ole 71. They found that it increased the time spend by mice in
the light compartment (233 ± 29 s) compared to the standard
reference drug imipramine (202 ± 22 s) which indicated its
potential anti-depressant and anxiolytic activity.
F3C

NH N
N N

Cl 71
Cl

Geronikaki et al. (2004) carried out design, synthesis,

69
Imidazoles in CNS disorders
Imidazoles in neurogenerative disorders
2-Amino-3-(3-hydroxy-methylisoxazol-4-yl)propionic acid
(AMPA) antagonists have gained special importance in
treatment of various neurogenerative diseases and can be
used as potential therapeutic targets for treatment of epi-
lepsy, spasticity, pain, and neurogenerative disorders. In
view of above, Abraham et al. (2000) synthesized some
imidazole derivatives as non-competitive AMPA antago-
computational, and biological evaluation of new anxiolyt-
ics. Among the synthesized compounds, 2-(4-nitrophenyl)-
3-(4-phenyl piperazino methyl) imidazo[1,2-a]-pyridine 72
and 2-(4-fluorophenyl)-3-(4-methyl piperazinomethyl) im-
idazo [1,2-a] pyridine 73 increased the number of punished
water licks to 800 ± 128 and 588 ± 66, respectively, when
compared to the standard drug medazepam (398 ± 52).
N
N
-
O
N+
N

nist. Compound 70 revealed an excellent anti-convulsant N

activity against seizures evoked by maximal electroshock O

(MES) at ED50 value of 24 mg/kg p.o. It was further found

to be highly active in treatment model of focal ischemia
predictive of a therapeutic value in human stroke. It also 72
reversed the dopamine depleting effect of MPTP and
antagonized the oxotremorine induced tremor in mice
indicating a potential of anti-parkinson activity. These
findings indicated that the non-competitive AMPA antag- N
onist 70 may have the therapeutical potential not only in N
acute but also in chronic neurogenerative disorders as well.

N N
F
N

Cl N
73

Imidazoles as miscellaneous agents

Imidazoles as skin whitening agents

H2 N

The biological activities of stem-cell factor (SCF) are

70 induced through its receptor, c-kit, which is expressed on
Med Chem Res
melanocytes in the skin. It is well known that c-kit is
related to pigmentation. In view of above, Na et al. (2007)
synthesized phenyl imidazole sulfonamide derivatives as
potent c-kit inhibitors and found [4-t-butylphenyl]-N-(4-
imidazol-1-yl-phenyl)sulfonamide 74 (ISCK03), to be most
active one in both in vitro as well as in vivo studies.
O
N
S N N
H GraBmann et al. (2003) synthesized a novel series of
O imidazole-containing compounds with dual properties, i.e.,
74
Imidazoles as anti-aging agents
Apart from genetically programmed cell aging, different
external aggressors related to oxidative stress and lipid
peroxidation (LPO) can accelerate the skin aging phenom-
enon. Oxidative stress associated with the formation of lipid
peroxides is suggested to contribute to pathological pro-
cesses in aging and systemic diseases known as the risk
factors for cataract. A series of related biocompatible
imidazole-containing peptidomimetics were synthesized to
confer resistance to enzymatic hydrolysis and ex vivo
improvement of protective anti-oxidative properties related
to l-carnosine 75. The included findings revealed a greater
role of N-acetylcarnosine (NAC) 76 and carcinine ex vivo in
the prolongation and potentiation of physiological responses
to the therapeutical and cosmetics treatments with l-carno-
sine as anti-oxidant. Universal anti-oxidant protective effect
of natural imidazole-containing peptidomimetics carcinine,
NAC, and l-carnosine was revealed. The products were
effective in protecting both hydrophilic biological molecules
(such as proteins, enzymes) as well as the lipophilic ones
(unsaturated fatty acids, membrane phospholipids). These
biocompatible mimetic actives, being well accepted in ex
vivo conditions in terms of the resistance to enzymatic
deactivation present the effective tool and active ingredients
with unusual anti-aging properties during the novel biolog-
ical skin and ophthalmic treatments. These actives will give
a growing place to anti-aging formulations with specific
protective and selective activities that fulfill professional and
common demand (Babizhayev, 2006).
O on [35S]GTPcS binding to rat brain membranes, and for
H
N H
N pig ileum (pKB). The pKi values of the derivatives with
NHCOCH3
N COOH
75
H
O
N H
N
NH2
N COOH
76
Imidazoles as H3 receptor antagonists
inhibitory potency at the enzyme histamine Ns-methyl-
transferase (HMT) and antagonist potency at histamine H3
receptors. Pharmacologically, these new hybrid drugs were
evaluated in functional assays for their inhibitory potencies
at rat kidney HMT and for their antagonist activities on
synaptosomes of rat cerebral cortex. For selected com-
pounds, binding affinities at recombinant human histamine
H3 receptors were also determined. The results showed that
the most interesting compound N-quinolin-4-yl-3-(1H-
imidazol-4-yl)propanamine dihydrogenoxalate 77, has a
highly potent H3 receptor ligand (Ki = 4.1 nM) as well
high potent HMT inhibitor (IC50 = 24 nM), which makes
this derivative a valuable pharmacological tool for further
development.
H
N
O O
OH
HO
OH N
HO O
O
N
HN
77
Mor et al. (2004) synthesized a new class of H3-antag-
onists, having a 2-aminobenzimidazole moiety connected
to the 4(5) position of an imidazole ring through di- or
tri-methylene chains. The compounds were tested for their
H3-receptor affinity, by displacement of [3H]-(R)-a-meth-
ylhistamine ([3H]-RAMHA) binding to rat brain mem-
branes (pKi), for intrinsic activity, evaluating their effect
H3-antagonist potency, on electrically stimulated guinea-
longer chain ranged over two orders of magnitude, with the
[3-(1H-imidazol-4-yl)propyl]-(5-methoxy-1H-benzoimidazol-
2-yl)amine 78 endowed with sub-nanomolar affinity (pKi =
9.37).

OCH3
HN
NH N
HN N of type 2 diabetes. Bioorg Med Chem 14:7419–7433
78
Conclusion
The aforementioned literature revealed that imidazole is a
versatile heterocyclic nucleus having high potential for the
development of new chemical entities for the treatment of
infectious diseases, cancer, metabolic, cardiovascular, and
CNS disorders as well as inflammatory conditions.
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