Med Chem Res (2012) 21:269–283
DOI 10.1007/s00044-010-9533-9
REVIEW ARTICLE
Benzimidazole: a medicinally important heterocyclic moiety
Balasubramanian Narasimhan • Deepika Sharma •
Pradeep Kumar
Received: 15 October 2010 / Accepted: 30 November 2010 / Published online: 25 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Benzimidazole nucleus is a constituent of many
bioactive heterocyclic compounds that are of wide interest
because of their diverse biological and clinical applica-
tions. Moreover, benzimidazole derivatives are structural
isosters of naturally occurring nucleotides, which allows
them to interact easily with the biopolymers of the living
system. This created interest in researchers who have
synthesized variety of benzimidazole derivatives and
screened them for their various biological activities, viz.,
anticancer, hormone antagonist, antiviral, anti-HIV,
anthelmintic, antiprotozoal, antimycobacterial, antihyper-
tensive, anti-inflammatory, analgesic, anxiolytic, antialler-
gic, coagulant, anticoagulant, antioxidant as well
antidiabetic activities.
Keywords Benzimidazole  Anticancer  Antiviral 
Antibacterial activity
Introduction
The incorporation of benzimidazole nucleus, a biologically
accepted pharmacophore in medicinal compounds, has
made it a versatile heterocyclic moiety possessing wide
spectrum of biological activities. Moreover, benzimidazole
derivatives are structural isosters of naturally occurring
nucleotides, which allow them to interact easily with the
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
biopolymers of the living system which is responsible for
their numerous biological activities and functions. In the
present study, we have made an attempt to collect bio-
logical properties of benzimidazole nucleus in the new
millennium.
Biological activities of benzimidazoles
Benzimidazoles in treatment of cancer
Benzimidazoles as anticancer agents
Cancer is a malignant disease characterized by uncon-
trolled proliferation of cells which may be rapid or slow,
depending on the type of cancer, a number of anticancer
drugs are currently in clinical practice. Benzimidazole
derivatives recently attracted medicinal chemists in
exploring their potential as anticancer agents.
Kumar et al. prepared a series of carbomethoxy-substi-
tuted benzimidazole derivatives of UK-1 [a bis (benzox-
azole) natural product] isolated from a strain of
Streptomyces and evaluated its cytotoxicity by Alamar
Blue cytotoxicity assays against MCF-7, HL-60, HT-29
and PC-3 cell lines. They found that the compound methyl
2-[2-(2-hydroxyphenyl)-1,3-benzooxazol-4-yl]-1H-benzi-
midazole-4-carboxylate, 1, exhibited cytotoxicity against
the tested cell lines with an IC50 value ranging from 7.0 to
100 lM (Kumar et al., 2002).
New styryl sulfones were screened for their anticancer
potential against different cell lines causing breast, CNS,
colon, lung, melanoma, ovarian, prostrate and renal cancer.
Among the compounds synthesized, 6-chloro-1H-
(benzo[d]imidazol-2-yl) methyl [(E)-2-(4-chloro-3-methyl
phenyl)-1-ethenyl] sulphone, 2, has shown 51% tumour
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270 Med Chem Res (2012) 21:269–283

growth inhibition in mice implanted with HT-29 human Benzimidazole-based metal complexes as anticancer
carcinoma at 400 mg/kg orally (Vedula et al., 2003). agents

Pt(II) complexes bearing 2-phenyl benzimidazole, 5, and 2-

mercapto methyl benzimidazoles, 6 and 7, were found to be
O S O
cytotoxic against human RD Rhabdomyosarcoma cell line
HO O
and less mutagenic against Salmonella thyphimurium
N N

-
strains TA 98 and TA 100, which made them to be con-
O
NH Cl
sidered as potential antitumour agents (Gumus et al.,
O N 2003).
NH

Cl

1 2
Four classes of UK-1 analogues were synthesized and Cl2Pt N NH

their cytotoxicity testing against human A-549, BFTC-905, Cl2Pt N NH

RD, MES-SA and HeLa carcinoma cell lines were deter-
mined. The anticancer screening results revealed that 20 -
(2-benzyloxy-phenyl)-1H,10 H-[2,4]-bibenzo imidazolyl-4-
carboxylic acid methyl ester, 3 (A-549 IC50 2.8 lM; HeLa
IC50 7.1 lM), is more potent than UK-1 (A-549 IC50
5.1 lM; HeLa IC50 10.7 lM) (Huang et al., 2006).
Ramla et al. in their study, synthesized 2-(1-benzyl-2-
methyl-1H-benzimidazol-5-ylimino)-3-(substituted)-thiaz-
olidines-4-ones and 3-(2-methyl-1H-benzimidazol-5-yl)-2-
substituted-thiazolidines-4-ones and evaluated their anti-
tumour potential against the Epstein–Barr virus early
antigen (EBV-EA) activation introduced by 12-O-tetra-
decanoyl phorbol-13-acetate. The results showed that 3-
benzoyl-2-(1-benzyl-2-methyl-1H-benzimidazol-5-yl-imino)
thiazolidin-4-one, 4, was found to be significantly active
(Ramla et al., 2007).
SR
2 2
5 6- R=H 7 - R=CH3
Benzimidazoles as protein kinase CK2 inhibitors
CK2 proteins are invariably more abundant in tumours as
compared to normal tissues and their over expression causes
neoplastic growth in animal and cellular models presenting
alterations in the expression of cellular oncogenes or tumour
suppressor genes. Pagano et al. described the synthesis and
CK2 inhibitory activity of 2-dimethylamino-4,5,6,7-tetrab-
romo-1H-benzimidazole (DMAT), 8, derivatives. From the

HN

N O

N N

HN O
N
N
O
N

S
O

3 4

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Med Chem Res (2012) 21:269–283 271

results, they observed that DMAT is superior to commonly
used specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole
(TBB) in several respects. DMAT displayed the lowest Ki
value ever reported for a CK2 inhibitor (40 nM) and it is cell
permeable (Pagona et al., 2004).
The CK2 inhibitory activity of 5,6-dichloro benzimid-
azole ribonucleoside stimulated Andrzejewska et al. to
synthesize polyhalogenobenzimidazoles. They evaluated
the synthesized derivatives for their CK2 inhibitory activity
using CK2 purified from rat liver cytosol and observed that
most efficient inhibition of CK2 is attained only if the
benzene ring of benzimidazole is tetrahalogenated which is
clearly evidenced by the Ki value of 4,5,6,7-tetrabromo-2-
trifluoromethyl benzimidazole, 9 (Ki = 0.60 lM) (And-
rzejewska et al., 2003).
anticancer therapy. Keeping this in mind McBride et al.
synthesized 3-benzimidazol-2-yl-1H-indazoles as inhibi-
tors of RTK and found that compounds 10 and 11 pos-
sessed favourable pharmacokinetics and exhibit impressive
tumour growth inhibition property against different cell
lines tested (Zien et al., 2003).
Benzimidazoles as topoisomerase inhibitors
In a study of some novel fused heterocyclic compounds as
eukaryotic topisomerase II inhibitors, it was observed that
5-methylcarboxylate-2-phenylthiomethylbenzimidazole, 12,
was more active than the reference drug etoposide
(McBride et al., 2006).

Br
Br

F H Br
Br N N

N F

N N
Br F Br
H

Br Br

8 9

H
N N

H S
N N
HN N
H3COOC
N
N

10 - R=6-OBn; 11 - R=4-NH(CO)NHt-Bu 12

Benzimidazoles as tyrosine kinase inhibitors
Tumour angiogenesis is the process that leads to the for-
mation of blood vessels in a tumour, which in turn supports
cancer cell survival, local tumour growth and development
of distant metastasis. The key mediator of this process is
vascular endothelial growth factor (VEGF) which binds to
its respective receptor tyrosine kinase (RTK) to promote
the proliferation, migration and survival of endothelial
cells. Therefore blocking, in particular, VEGF signalling
through these receptors has become an attractive target for
DNA topoisomerase are ubiquitous enzymes that control
and modify the topological states of DNA (Pinar et al., 2004).
Jin et al. synthesized a series of 20 -heterocyclic derivatives of
5-phenyl-2,50 -1H-bibenzimidazoles, 13, and evaluated them
for their topoisomerase I poisoning activity and cytotoxicity.
From their study, they observed that topoisomerase I poi-
soning activity was associated with 20 -derivatives that pos-
sessed a hydrogen atom capable of hydrogen bond formation,
suggesting that the interatomic distances between such
hydrogen atoms and the heteroatoms on the adjacent benz-
imidazole influence the activity (Jin et al., 2000).

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272 Med Chem Res (2012) 21:269–283

N R
N N N
H3C
H

NH

13

Benzimidazoles in treatment of infectious diseases
Benzimidazole exhibited activity against wide variety of
pathogenic viruses including human immunodeficiency
virus (HIV). Some of the recent literature corresponding to
the antiviral spectrum of benzimidazole derivatives can be
categorized as follows.
Benzimidazoles as antiviral agents
Clercq and Naesens in their search for effective anti-HHV-
6 agents synthesized some nucleoside and non-nucleoside
Starcevic et al. prepared a set of heterocyclic benz-
imidazole derivatives bearing amidino substituents at C-5
of benzimidazole ring, by introducing various heterocyclic
nuclei (pyridine, N-methyl pyrrole or imidazole) at C-2
and evaluated their antiviral activity towards coxacaki-
eviruses and echoviruses. Fairly strong activity was
observed with 2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimi-
dazole-5-carboxamidine hydrochloride, 16, and n-iso-
propyl-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine,
17, towards adenovirus, which make them to be consid-
ered as leads against adenoviral replication (Starcevic
et al., 2007).

NH
N OH

N
OH
H Cl
N
Cl O
Br
OH
N
Cl Cl

14 15
NH

NH
N
H2 N
HCl N
N
H
N N
H
N N
H

16 17

analogues of benzimidazoles. In non-nucleoside analogues, Benzimidazoles as antihepatitic agents

2-bromo-5,6-dichlorobenzimidazole, 14, and 1-(b-L-ribo-
furanosyl)-2-isopropyl amino-5,6-dichlorobenzimidazole, Hepatitis B virus infection is the world’s ninth leading
15, were found to be active ones (Clerq and Naesens, 2006). cause of death and responsible for both acute and chronic

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Med Chem Res (2012) 21:269–283
hepatitis. N-(2-amino-1-(propane-2-sulfonyl)-1H-benzo[d]-
imidazol-6-yl)-2,6-difluoro-benzamide, 18, and N5,N5-bis-
(3-methoxy-benzyl)-1-(propane-2-sulfonyl)-1H-benzimid-
azole-2,5-diamine, 19, emerged as potent antiviral agent
with IC50 value of 0.7 lM during identification of 1-iso-
propylsulfonyl-2-amine benzimidazoles as a new class of
hepatitis B virus inhibitors (Li et al., 2007).
Ishida et al. synthesized a series of 1-cycloalkyl-2-
phenyl-1H-benzimidazole-5-carboxylic acid derivatives
and evaluated their inhibitory activity against hepatitis C
virus NS5B RNA-dependent RNA polymerase. In their
study, they found that diaryl methoxy derivatives, 20 and
21, blocked the replication of subgenomic HCV-RNA in
the replicon cells (Ishida et al., 2006).
O
N N
O
N O
O
N NH2
18
HOOC
N
O NH2
N Ar
20 - R = H; 21 - R = F
Benzimidazoles as anti-HIV agents
Middleton et al. synthesized HIV Type I integrase inhibi-
tors using naphthamidines and 2-aminobenzimidazoles and
found that A-201735, 22, emerged as a potent integrase
inhibitor (Middleton et al., 2004).
273
Benzimidazoles as antienteroviral agents
Palma et al. synthesized a series of 2,6-dihalophenyl-
substituted 1H,3H-thiazolo[3,4-a] benzimidazoles and
screened their anti-enterovirus activity against cox-
sackievirus A9, echovirus 9 and 11 and all six
strains of coxsackievirus B. From their study, they con-
cluded that 1-(2-chloro-6-fluorophenyl)-6-trifluoromethyl-
1H,3H-thiazolo[3,4-a] benzimidazole, 23, was a promis-
ing candidate in a dose-dependent inhibition of viral
replication with a 50% effective concentration (EC50) of
0.41 lg/ml without any detectable cytotoxicity at the
highest concentration (100 lg/ml) tested (Palma et al.,
2007).
O2S
H3CO N
NH2
N
OCH3
19
NH2
H
Ar
1 N
2
N
22
Benzimidazoles as anti-RSV agents
Respiratory syncytial virus (RSV), a paramyxovirus, is an
important cause of respiratory tract infection in infants,
young children and adults. Andries et al. synthesized
and screened more than 300 analogue-substituted
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benzimidazoles for their antiviral activity against RSV and
identified JNJ 2408068 (R170591), 24, a low molecular
weight (MW 395) derivative with an EC50 value of
0.16 nM against some lab strains which is almost 1,00,000
times better than that of ribavirin (15 lM) (Andries et al.,
2003).
S
Cl
N
N N
H
F HN
F F
F OH
23
NH
Cl
N H2N
Cl
N
Cl
NH
Cl
25
Benzimidazoles as antibacterial agents
Almost all the major classes of antibiotics have encoun-
tered resistance in clinical application. The emergence of
bacterial resistance to b-lactum antibiotics, macrolides,
quinolones and vancomycin is becoming a major world-
wide health problem. Recent literature review revealed that
benzimidazole derivatives have emerged as promising
candidates for the development of antibacterial agents.
He et al. synthesized 2-piperidin-4-yl-benzimidazoles and
screened for their broad spectrum antimicrobial activity
against various strains of microorganisms such as Entero-
coccus, C. albicans and P. aeruginosa. From their study, they
found that compound 25, N1-[4-(5,6-dichloro-2-piperidin-4-
yl-benzoimidazol-1-ylmethyl)-benzyl]-ethane-1,2-diamine
emerged as promising antibacterial agent (He et al., 2003).
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Med Chem Res (2012) 21:269–283
In another study, a series of novel benzimidazole deriv-
atives were synthesized by parallel solution-phase chemistry
and screened for their antibacterial activity against variety of
microorganisms. The results of antibacterial study suggested
that compound 26 is one of the most effective antibacterial
agent among synthesized compounds (He et al., 2004).
N
N
N
NH2
24
NH
NH
NH
O
O
N
NH
N
26
Goker et al. synthesized a series of novel 1,2-disubsti-
tuted-1H-benzimidazole-N-alkylated-5-carboxamidine deriv-
atives and evaluated for their in vitro antibacterial
activities against S. aureus and methicillin resistant
S. aureus by tube dilution method. The results showed
that compounds having 3,4-dichloro-substituted phenyl at
position C-2 of N-bulky alkyl-substituted benzimid-
azole carboxamidines, 27, exhibited the greatest activity
with MIC values of 1.56–0.39 lg/ml (Goker et al.,
2005).
Kumar et al. synthesized some novel 2-(6-fluorochroman-
2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles derivatives, 28,
and evaluated against different antibacterial agents. Among
the synthesized compounds, some exhibited promising
antibacterial activity against Salmonella typhimurium
(Kumar et al., 2006).
Med Chem Res (2012) 21:269–283 275

R' R2 R3

N R

R4 N O F
"RHN N

R6 R5 N
NH HCl

27 28

Benzimidazoles as antifungal agents
A series of 2-substituted phenyl-1H-(5-substituted) benz-
imidazole were prepared and evaluated in vitro against
Candida species. The results of antimicrobial studies sug-
gested that cyano-substituted compounds especially com-
agents targeting fungal N-myristoyl transferase. Among the
new inhibitors synthesized, benzimidazole derivative, (1-
allyl-1H-benzimidazol-2-yl)-[4-(3-benzylamino-propoxy)-
3-methyl-benzofuran-2-yl]-methanone, 30, showed clear
antifungal activity in murine systemic candidiasis model
(Kawasaki et al., 2003).

N
H

O
N N
N
F

N
NC

29 30

pound 29, 1-butyl-2-(4-fluoro-phenyl)-1H-benzimidazole-5- Benzimidazoles as anthelmintic agents

carbonitrile, exhibited greatest activity with MIC value of
3.13 lg/ml, similar to that of fluconazole (Goker et al., 2002).
N-myristoyltransferase is an enzyme that transfers the
myristoyl group of myristoyl CoA to the N-terminal glycine
of various eukaryotic cellular proteins. N-myristoylation of
proteins Gpa 1, Arf 1, Arf 2 and Vps 15, which are essential
for fungal growth, has been reported to be indispensable for
their function in Saccharomyces cerevisiae. Kawasaki et al.
synthesized novel benzofuran derivatives as antifungal
Many benzimidazole derivatives are widely used for the
treatment of parasitic diseases. In light of above, Mavrova
et al. synthesized 5(6)-(un) substituted-1H-benzimidazol-2-
yl thioacetyl piperazine derivatives and evaluated their
anthelmintic activity against Trichenella spirilis. From the
study, it was evident that 2-(2-{2-[4-(4-chlorophenyl)pip-
erazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1H-benzimid-
azole, 31, was the most active one (Mavrova et al., 2006).

H3C H
N
N N Cl
S

N O

31

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Benzimidazoles as antiamoebic agents Benzimidazoles as antiprotozoal agent

Amoebiasis is a world-wide parasitic disease and a public
health problem in developing countries, which is respon-
sible for up to 1,00,000 deaths/annum. In search of better
antiamoebic agents, Sondhi et al. reacted substituted
o-phenylenediamines with 3-isothiocyanatobutanal to give
pyrimidobenzimidazole derivatives. Among the synthe-
sized compounds, pyrimido [1,6-a] benzimidazole-
1(2H) thione, 32, exhibited good in vitro antiamoebic
activity (Sondhi et al., 2002).
Vallezo et al. performed comparative molecular field
analysis (COMFA) on a set of 1H-benzimidazole deriva-
tives, 33, to determine the tautomeric form that would
probably fit a target receptor in E. histolytica. The results
suggested that the antiamoebic activity is favoured with
steric bulk at position 5 of benzimidazole ring and low
electron density on group at position 2 (Lopez-Vallezo
et al., 2007).
In a study of synthesis and antiprotozoal activity of 5-
substituted 4,6-dibromo-2-mercapto benzimidazole deriv-
atives, 34, it was observed that the new compounds syn-
thesized were at least several times more active against
Giardia intestinalism (IC50 = 0.006–0.053 lg/ml) and a
half of them were at least several times more active against
Trichomonas vaginilis (IC50 = 0.0015–0.182 lg/ml) than
metronidazole (Andrzejewska et al., 2004).
Ismail et al. synthesized a series of biphenyl benz-
imidazole diamidines from their respective diamidaoximes,
through the bis-O-acetoxyamidoxime followed by hydro-
genation in glacial acetic acid/ethanol in the presence of
Pd–C and evaluated their antiprotozoal activity against
Plasmodium falciparum. From the synthesized compounds,
2-(40 -amidino-4-hydroxybiphenyl-3-yl)-1H-benzimidazole-
5-amidine acetate salt, 35, showed excellent activity with
an IC50 value of 2.1 nM (Ismail et al., 2004).

HO

R2 H
N
N
SR3
H2 N

N NH NH2

HN
R1 NH

34 35

Benzimidazoles as antimycobacterial agents

R4
S R5
NH
R3
Klimesova et al. synthesized a series of 2-alkyl sulphanyl
N
HOOC
N
CH3 benzimidazoles and screened them for their antimycobacterial
R6
activity. Among the synthesized compounds, 36, 2-(3,5-dini-
N
R2
N tro-benzylsulfanyl)-1H-benzoimidazole, emerged as most
active compound against M. kansasii and M. avium in com-
H R1
parison to standard drug isoniazid, while it shows comparable
32 33 activity against M. tuberculosis (Klimesova et al., 2002).

H NO2 CH2OEt O H
N
F
N N
S
N
N O

NO2

36 37

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Benzimidazoles as centrally acting agents
Jordan et al. reported the synthesis of series of pyrido[1,2-a]
benzimidazoles (PBIs) substituted at N5-nitrogen and
screened their affinity for benzodiazepine site on the GABA-
A receptor. The outcome of the study revealed that ethoxy-
methyl analogue, i.e. 5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-
tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylic
acid (2-fluoro-phenyl)-amide, 37, as promising anxiolytic
agent with an IC50 value of 0.1 nM, which has been advanced
to human clinical trials (Jordan et al., 2002).
Corticotropin-releasing factor (CRF) is a 41-amino acid
neuropeptide secreted in the hippocampus. It imposes its
physiological effects on depression and other neuropsy-
chiatric disorders. Han et al. synthesized some imi-
dazo[1,2-a] benzimidazoles as CRF1R antagonists and
found that compound 38, cyclopropylmethyl-propyl-[2-
trifluoromethyl-4-(2,4,5-trimethyl-benzyl)-4H-benzo[d]pyr-
rolo[1,2-a]imidazol-1-yl methyl]-amine, has the potential
to be used as anxiolytic agent (Han et al., 2005).
CH2CH2CH3
N
N
N CH3
F3C
H3C
CH3
38
Benzimidazole in treatment of metabolic disorders
Benzimidazoles in control of obesity
The MCH R1 receptor has been investigated thoroughly for
its possible role in regulating eating behaviour in mam-
mals. MCH-deficient mice have reduced body weight and
are lean due to hypophagia. In view of above, Wu et al.
synthesized novel benzimidazole analogues and evaluated
them for their MCHR1 antagonistic activity. 40 -[(1-
Cyclopropylmethyl-piperidin-4-ylidene)-(5-fluoro-6-tri-
fluoromethyl-1H-benzoimidazol-2-yl)-methyl]-biphenyl-3-
carbonitrile, 39, and 40 -[(1-cyclopropylmethyl-piperidin-4-
ylidene)-(5,6-dichloro-1H-benzoimidazol-2-yl)-methyl]-biphe-
nyl-3 carbonitrile, 40, have been demonstrated to be full
MCHR1 antagonists in a functional assay with Kb value of
25 and 70 nM, respectively (Wu et al., 2006).
277
CN CN
F Cl
N CF3 N Cl
N N
H H
N N
39 40
Benzimidazoles as antidiabetic agents
3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulphonyl)-3H-
benzimidazole-5-carbo xamide (FK614), 41, improves
insulin resistance in C57BL/KSJ-db/db mice (db/db mice)
animal models through activation of PPARc-mediated
transcriptional activity which makes it to be a novel ther-
apeutic candidate for treatment of Type II diabetic patients
(Minoura et al., 2004).
Cl
N
O N
S NH Cl
O
O
41
Benzimidazoles as cardiovascular agents
Benzimidazoles as antihypertensive agents
Hypertension, defined as an elevation of systolic and/or
diastolic blood pressure to above 140/90 mmHg. In a study
relaxant activity of 2-(o,p-substituted phenyl)-1H-benz-
imidazole derivatives with various 5- and 6-position sub-
stituents (–H, –CH3, –NO2, –CF3) was recorded using the in
vitro rat aorta ring test. Compounds 42 and 43, [2-(5-nitro-
1H-benzimidazol-2-yl) phenol] and 2-(4-methoxyphenyl)-
5-nitro-1H-benzimidazole, respectively, were found to be
the most potent compound of the series, showing IC50 value
of 0.95 and 1.41 lM (with endothelium) and 2.01 and
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278 Med Chem Res (2012) 21:269–283

3.61 lM (without endothelium), respectively (Estrada-Soto bodies. Platelets are essential in the process of blood
et al., 2006). clotting and repair of damaged blood vessels. Literature
HO report revealed that benzimidazole analogue, 5-{2-[5-(4-
H H
N N tert-Butyl-phenyl)-furan-2-yl]-3H-benzoimidazol-5-ylmethyl-
OCH3
ene}-2-thioxo-thiazolidin-4-one, 45, was found to be the
N N
O 2N O2N most potent one with a percentage TOP agonist efficacy of
42 43 142% (Safonov et al., 2006).

S
O
HN

HO S
O
N

N H
O
N O

NH2

44 45

Shah et al. synthesized a series of 5-(alkyl and aryl) Benzimidazoles as anticoagulants

carboxamido benzimidazole derivatives and evaluated for
their in vitro angiotensin II-AT1 receptor antagonistic
activity as well in vivo antihypertensive activities. Among
the synthesized compounds, compound 40 -(2-butyl-5-pro-
pionyl amino-benzimidazol-1-ylmethyl)-biphenyl-2-car-
boxylic acid, 44, has decreased mean arterial B.P. by
36.2 ± 1.9 mm of Hg. They further suggested that phar-
macological activities were inversely related to the size of
alkyl and aryl substituents (Shah et al., 2008).
Benzimidazoles as coagulants
Thrombopoietin (TPO) plays a critical role in the produc-
tion of platelets by stimulating the proliferation of megakar-
yocytes progenitor cells into fully mature megakaryocytes,
which then undergo fragmentation to produce platelet
Thrombin (fIIa), a multifunctional serine protease with
trypsin like specificity, plays a central role in thrombosis
and hemostasis by regulating the blood coagulation cas-
cade and platelet activation. Development of thrombin
inhibitors will help in the development of anticoagulant.
In view of above, Cui et al. reported the benzimidazole-
based compound, C-[1-(tetrahydro-pyran-2-yl)-1H-ben-
zoimidazol-5-yl]-methylamine, 46, as potent thrombin
inhibitors (Cui et al., 2002).
He et al. explored the systemic replacement of a key
chlorobenzothiophene group in a novel series of nanomolar
factor Xa inhibitors with benzimidazole and its isosters and
found that these type of compounds, especially 47, are very
selective against factor Xa over other serine proteases (He
et al., 2002).

THP
NH2
N
R N
M
N
Z
N
N N
NH2 H

46 47

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Med Chem Res (2012) 21:269–283
Benzimidazole as analgesic and anti-inflammatory
agents
Capsaicin has ability to activate mammalian nociceptors and
thus cause pain. The mechanism for this is now known to be
the result of gating of the transient receptor potential TRPV1
vanilloid receptor, originally known as VR1 receptor. Thus,
antagonism of TRPV1 receptor may cause treatment of both
inflammatory and neuropathic pain. Keeping this in mind,
Shao et al. synthesized a series of 4-(2-pyridyl) piperazine-
1H-benzimidazole analogues and evaluated for TRPV1
antagonistic activity. From the study, 6-tert-butyl-2-[4-(3-
chloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-1H-benzo-
imidazole, 48, emerged as potent TRPV1 antagonist with
IC50 value of 104 nM (Shao et al., 2005).
In another study, for search of novel TRPV1-antagonist
using carrageenan-induced thermal hyperalgesia model com-
pound 49, 2-(4-trifluoromethyl-phenyl)-6-(3-trifluoromethyl-
pyridin-2-yl)-1H-benzoimidazole, showed comparable affinity
at the hTRPV1 receptor with an hIC50 value of 22 nM as
measured in a FLIPR-based assay whole cell patch clamp
experiments were again used to confirm activity against pH 5.5-
dependent activation of the human receptor and show per-
centage inhibition of 95% at 100 nM (Fletcher et al., 2006).
H CF3
N N
N N
N
Cl
48
O
N N
N
N S
O H
N
NH2
O
50
279
Interleukin-2-inducible T cell kinase (ITK), also known
as T cell specific kinase (TSK) is a member of Tec family
of protein tyrosine kinase. Stimulation of T cell receptor
(TCR) causes its activation which in turn is responsible for
production of different interleukins which causes inflam-
matory response. Thus, inhibition of ITK may act as useful
target in design of anti-inflammatory agents. Snow et al. in
search of novel class of kinase inhibitors synthesized a
series of benzimidazole derivatives and evaluated their
anti-inflammatory potential. From the study, it was evident
that compound 50, thiophene-2-carboxylic acid [1-(2-car-
bamoyl-ethyl)-5-(cyclohexanecarbonyl-methyl-amino)-1H-
benzoimidazol-2-yl]-amide, possessed a high ITK inhibi-
tory activity (Snow et al., 2007).
P38a plays a dominant role in pathogenesis of acute and
chronic inflammatory responses. Activation of p38a occurs
in monocytes and macrophages under different stress-
related stimuli. Subsequent phosphorylation of downstream
effectors and transcriptional factors leads to the biosyn-
thesis of potentially deleterious pro-inflammatory cyto-
kines such as TNFa and IL-1b. In view of above, Mader
et al. synthesized a series of imidazolyl benzimidazoles,
51, and found that few of them were potent p38a MAP
kinase inhibitors (Mader et al., 2008).
N
F3C
N
H
N
49
H NH2
N
O S O
R1
N
R2
51
123
280
Benzimidazoles as hormonal modulators
Benzimidazoles as progesterone receptor agonist
Progesterone plays an important role in reproductive
physiology, as well as bone metabolism and neurotropic
functions. Synthetic steroidal progestins are widely used as
therapeutic agents in the control of fertility, combination
hormonal replacement therapy and variety of endocrino-
logic diseases. Dong et al. in their search of a selective
nonsteroidal progesterone receptor agonist identified that
compound 52, 1-cyclopentyl-6-imidazol-1-yl-1H-benzo-
imidazole-2-thiol, binds to human progesterone receptor
with high affinity (Ki = 28 nM) (Dong et al., 2004).
Cl
N
OH
N CF3
Cl
H
54
Benzimidazoles as hormonal antagonist
Luteinizing hormone releasing hormone (LHRH) antagonists
have been investigated by many groups as potential candi-
dates for treatment of hormone-dependent diseases, such as
endometriosis, breast cancer and prostrate cancer. Tatsuta
et al. in their study reported that 1-tert-Butyl-3-[2-(2-meth-
oxy-5-nitro-benzylsulfanyl)-1-propyl-1H-benzoimidazol-5-
yl]-urea, has potent functional antagonism on human LHRH
receptor (IC50 = 0.073 lg/ml) (Tatsuta et al., 2005).
N N
N
SH
N H
H
N OMe
52
123
Med Chem Res (2012) 21:269–283
Ng et al. synthesized 2-(2,2,2)-trifluoroethyl benzimid-
azole derivatives as potent and tissue selective androgen
receptor modulators (SARMs) and found 2-(5,6-dichloro-
1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-ol,
54, possessed both good muscle agonism and prostate
inhibition (Ng et al., 2007a, b).
The synthesis and in vivo SAR studies of N-benzyl, N-
aceto and N-ethylene ether derivatives of 2-(2,2,2-trifluro-
ethyl)-5,6-dichloro benzimidazole as novel androgen
receptor antagonists led to the discovery of 4-bromobenzyl
benzimidazole, 55, as a more potent androgen receptor
antagonist in the rat prostrate (ID50 = 0.13 mg/day),
compared with bicalutamide (ID50 = 0.23 mg/day) (Ng
et al., 2007a, b).
N
NH
Br
55
Benzimidazoles as antiallergic agents
Nokano et al. synthesized a series of novel benzimidazole
derivatives and screened for their antiallergic potential with
5-lipoxygenase inhibiting action. 1[2-[2-(4-hydroxy-2,3,5-
trimethylphenoxy)ethoxy]ethyl]-2-(4-methyl-1-homopiper-
azino)-H-benzimidazole fumarate (BOM1006), 56, exhib-
ited a dose-dependent suppressive action on 48 h homol-
ogous passive cutaneous anaphylaxis (PCA) reaction in rats
(Nokano et al., 2000).
CH2CH3 NO2
N
O
S
N
N
53
Med Chem Res (2012) 21:269–283
N SMe
N CH3
N
N N
CH2CH2OC2H4O
OH
56
The symptoms of allergic rhinitis are multifactorial and
induced by action of a variety of lipid mediators, of which
histamine, cysteniyl leukotrienes (Cys-LTs) and prosta-
glandin D2 (PGD2) are considered as most important.
Beaulieu et al. synthesized a selective DP antagonist which
might be of therapeutic value for allergic rhinitis. They
synthesized a series of 2-substituted N-benzyl benzimi-
dazoles and screened them for their human DP-receptor
antagonistic properties. From the pharmacological screen-
ing they observed that 4-{2-[1-(4-chloro-benzyl)-1H-ben-
zoimidazol-2-yl]-vinyl}-benzoic acid methyl ester, 57, and
4-{2-[1-(4-chloro-benzyl)-1H-benzoimidazol-2-yl]-ethyl}-
benzoic acid methyl ester, 58, were identified as potent DP
antagonists with improved selectivity at thromboxane A2
receptor and are worthy of further investigation (Beaulieu
et al., 2004).
Cl Cl
N N
N N
COOCH3
COOCH3
57 58
Benzimidazoles as CD-45 antagonist
Development of CD-45 inhibitors is useful for the treat-
ment of several immune diseases. Keeping this in mind,
Hamagnehi et al. screened 2-[(4-methylthiopyridin-2-
yl)methylsulpfinyl]benzimidazoles as protein tyrosine
phosphatase inhibitor. The synthesized compounds exhib-
ited potent inhibitory effects against protein tyrosine
phosphatase activity of CD-45. In particular, compound 59,
2-(4-methylsulfanyl-pyridin-2-ylmethanesulfinyl)-5-propoxy-
1H-benzoimidazole, had high specificity for CD-45 com-
pared with serine/theronine phosphatases, tyrosine pho-
phatases and dual phosphatase (Hamaguchi et al., 2000).
281
H O
S
N
N
O
59
Conclusion
The aforementioned literature revealed that benzimidazole
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 inflammatory conditions.
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