European Journal of Medicinal Chemistry 97 (2015) 419e443

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Structure activity relationship (SAR) study of benzimidazole scaffold

for different biological activities: A mini-review
Geeta Yadav*, Swastika Ganguly
Department of Pharmaceutical Science and Technology, Birla Institute of Technology, Mesra, Ranchi 151001, India

a r t i c l e i n f o a b s t r a c t

Article history: Benzimidazoles are the fused heterocyclic ring systems which form an integral part of vitamin B12 and
Received 27 September 2014 have been luring many researchers all over the world to assess their potential therapeutic significance.
Received in revised form They are known for their crucial role in numerous diseases via various mechanisms. Substitution of
23 November 2014
benzimidazole nucleus is a crucial step in the drug discovery process. Therefore, it is necessary to gather
Accepted 25 November 2014
Available online 26 November 2014
the latest information along with the earlier information to understand the present status of benz-
imidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different
pharmacological activities are described on the basis of SAR study using structural substitution pattern
Keywords:
Anthelmintics
around the benzimidazole nucleus and aims to review the reported work related to the chemistry and
Benzimidazole pharmacological activities of benzimidazole derivatives during recent years. The present manuscript to
Heterocyclic ring systems the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure
Pharmacological activities eactivity relationships of benzimidazole reported to date.
SAR study © 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction thiabendazole as antihelmintics; omeprazole, lansoprazole, pan-

toprazole as proton pump inhibitors; astemizole as antihistaminic;
Benzimidazole moiety came in picturesque in the 1950s after enviradine as antiviral; candesarten cilexitil and telmisartan as
the news that 5,6-dimethyl-l-(a-D-ribofuranosyl) benzimidazole is antihypertensives and many lead compounds in a wide range of
an integral part of the structure of the vitamin B12 [1]. Then in early other therapeutic areas.
sixties, it was originally developed as plant fungicides and later as Reported literature have shown the various substituted de-
veterinary anthelminthics [2]. The first benzimidazole to be rivatives of benzimidazole nucleus exhibiting remarkable biological
developed and licensed for human use was thiabendazole in 1962. activity as antitumor/antiproliferative/anticancer activity [3e14],
Further, a number of veterinary anthelminthics were developed antimicrobial including anti-HIV [15e19], antioxidant [20e23] and
and marketed, including parbendazole, fenbendazole, oxfendazole cysticidal activities [24].
and cambendazole. The first benzimidazole carbamate to make its
use in humans was mebendazole, followed by flubendazole. Even
some of the derivatives of benzimidazole have been clinically
2. Chemistry and synthetic strategies
approved as summarized in Fig. 1, like albendazole, mebendazole,
After going through an early review, it came to revelation that
the very first benzimidazole (2,5 or 2,6-dimethylbenzimidazole)
Abbreviations: NPY, neuropeptide; CYP450, cytochrome P450; HBV, hepatitis B was synthesized in 1872 by Hoebrecker through reduction of 4-
virus; HCV, hepatitis C virus; RSV, respiratory syncytial virus; VV, varicella virus;
methyl-2-nitroacetanilide (Scheme 1). After several years Laden-
BVDV, bovine viral diarrhea virus; CVB, coxsackie virus B; YFV, yellow fever virus;
MIC, minimum inhibitory concentration; GKAs, glucokinase activators; PK, protein burg obtained the same compound by refluxing 3,4-
kinase; PDE, phosphodiesterase; DPPH, 2,2,-diphenyl-1-picrylhydrazyl; NO, nitric diaminotoluene with acetic acid (Scheme 2) as shown in Fig. 2.
0
oxide; ABTS, 2,2 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); AChE, ace- Benzimidazoles were also known as benziminazoles and benzo-
tylcholinesteras; BuChE, butyrylcholinesterase; DGAT, diacylglycerol acyl trans- glyoxalines. These were also named as derivatives of o-phenyl-
frase; SAR, structure activity relationship; MTB, mycobacterium tuberculosis; INHR-
MTB, isoniazid resistant-mycobacterium tuberculosis.
enediamine. One major fact also came into light that hydrogen atom
* Corresponding author. at N-1 of the nucleus readily tautomerises which is responsible for
E-mail address: [email protected] (G. Yadav). isomerization in the derived compounds [25] as depicted in Fig. 3.

http://dx.doi.org/10.1016/j.ejmech.2014.11.053
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.
420 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443

Fig. 1. Benzimidazole containing clinically approved drugs.

Fig. 2. Shows the first schemes used for the synthesis of benzimidazoles.

A number of synthetic strategies have been effectively intro- heteroaromatic 2-nitroamines, formic acid, iron powder, and NH4Cl
duced in the past years. Numerous synthetic strategies for the for the reduction of nitro group and imidazole cyclization (C) using
synthesis of benzimidazole (A) have been outlined in Fig. 4. Nguyen one pot procedure [27]. Yang et al. developed a new method for the
et al. used elemental sulfur as oxidizing agent in the synthesis of synthesis of 2-substituted NeH, N-alkyl, and N-aryl benzimidazoles
benzazoles from alkylamines [26] (B). Hanan et al. in 2010 syn- in one step via the reduction of o-nitroanilines (D) in the presence
thesized bicyclic 2H-benzimidazoles by employing aromatic and of aldehydes and Na2S2O4 [28]. Cui et al. in 2012 reported another
method for the synthesis of 2-substituted benzimidazoles from 1,
2-phenylenediamines and triacyloxyborane intermediates which in
turn was obtained from the reaction of carboxylic acids (E) and
borane-THF [29].
In 2009, Sluiter and Christoffers prepared N-methyl-
benzimidazole using carbonitriles (F), N-methyl-1, 2-
phenylenediamine and sodium hydride as the starting materials
Fig. 3. Tauotomerism in benzimidazole.
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Fig. 4. Synthetic approaches for benzimidazoles.

[30]. In 2010, Wray synthesized (1) from common arylamino ox- presence of acidic conditions or heating to produce substituted 1H-
imes in the presence of different bases but among all bases, trie- benzimidazoles [34].
thylamine (G) promoted the synthesis of benzimidazoles [31]. Peng Kim et al. in 2011 synthesized the benzimidazole derivatives by
et al. carried out a highly economical and environment friendly condensation and CeN bond formation. One pot reaction starting
synthesis of benzimidazoles using water, Cu2O, DMEDA, and K2CO3 materials used were 2-haloanilines, aldehydes, NaN3, and CuCl (J)
(H) for the intramolecular N-arylation [32]. Saha et al. synthesized in catalytic amount [35]. 2-substituted benzimidazoles were syn-
substituted benzimidazoles, 2-aminobenzimidazoles via intra- thesized and at present are also undergoing by various different
molecular cyclization of o-bromoaryl derivatives (I) using Cu2O procedures using different catalyst viz., Bahrami et al. in 2007
nanoparticles as catalyst. In addition to it, the catalyst could be carried out synthesis of 2-substituted benzimidazoles by one-pot
recovered without any change in activity [33]. Diao et al. used CuI/L- condensation of o-phenylenediamines with aryl aldehydes using
proline as catalyst that causes coupling of aqueous ammonia with H2O2 and HCl (K) in acetonitrile [36]. Another method used was by
2-iodoacetanilides, which in turn undergo cyclization in the reaction of phenylenediamines and aldehydes in the presence of
iodine [37]. Reaction of 1, 2-phenylenediamine and an aldehyde in

Fig. 5. SAR of benzimidazole derivatives as HBV inhibitors.

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Fig. 6. SAR of amine substituted N-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-8-quinolamines.

the presence of oxone resulted in formation of benzimidazoles [38]. trichloroethyl imidates (M) as the acylating agents. For slow cycli-
Venkatesh et al. reported synthesis of different heterocycles from zation sodium acetate was the best choice [41]. Bahrami et al. re-
polarized ketene dithioacetals (versatile synthons) under different ported a new method that takes less reaction time and gives
conditions. Self condensation of ketene dithiolates occurred in the excellent yield of 2-substituted benzimidazoles [42] while She et al.
presence of K2CO3 which resulted in the formation of substituted carried out the reaction of o-amino anilines, terminal alkynes and
thienothiophene derivatives while in the presence of piperidine p-tolylsulfonyl azide for the synthesis of (A) in good yields [43]. Lv
and appropriate nucleophiles, a number of tris-heterocyclic com- et al. in 2009 carried out Cu (I)-catalyzed CeN coupling reaction of
pounds and bis-benzoxazolyl/benzothiazolyl/ o-haloarylcarbodiimides and N- or O-nucleophiles for the synthesis
benzimidazolylmethylthiomethylenepyrazolidinediones/ of (A) [44].
isoxazolidinediones/pyrimidinetriones/thioxopyrimidinediones
were obtained [39].
3. Biological activities
In 2012, Bastug et al. yielded benzoxazole, benzothiazole, and
benzimidazole derivatives by reaction of ortho-substituted anilines
The biological activities of benzimidazole involve various
(L) with functionalized orthoesters [40]. Caron et al. in 2012 carried
mechanisms like oxidative stress, enzymatic action, receptor
out synthesis of benzimidazoles and imidazopyridines using 2,2,2-
mediated mechanism etc. The biological investigations have
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Fig. 7. SAR of novel N-substituted benzimidazole CXCR4 antagonists.

revealed that substitution of various groups on the ring imparts Gudmundsson et al. synthesized some amine substituted N-
different activities. (1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-8-
quinolinamines 2e8 and evaluated them for anti-HIV-1 activity as
CXCR4 antagonists having potent activity against HIV-1 as
3.1. Antiviral activity demonstrated in Fig. 6 [46].
Miller et al. in 2010 reported some new types of stereochemi-
Benzimidazole and their derivatives exhibit antiviral activity via cally defined N-substituted benzimidazoles containing cyclic amine
interaction with different enzymes such as human cytomegalovirus side chains, and screened them for CXCR4 antagonists as anti-HIV
(HCMV), human herpes simplex virus (HSV-1), human immuno- agents. Amongst the series, compound 9 exhibited potent activity
deficiency virus (HIV), and hepatitis B and C virus (HBV and HCV). [47]. SAR study of these types of derivatives is shown in Fig. 7.
Luo et al. explored the hepatitis B virus (HBV) activity and cyto- Beaulieu et al. reported some benzimidazole-based allosteric
toxicity of novel benzimidazole derivatives in the HepG2.2.15 cell inhibitors of HCV NS5B that bind to thumb pocket I of the HCV NS5B
line. Compound 1, with IC50 < 0.41 mM and SI > 81.2 surfaced out as polymerase. The SAR study on three benzimidazole sub-series of
the most promising one. Its cytotoxicity (CC50 ¼ 33.3 mM) was over NS5B inhibitors suggested a common binding mode of these mol-
six times less than lamivudine (CC50 ¼ 5 mM), it had nearly three ecules to the enzyme is illustrated in Fig. 8 [48].
times higher selectivity than lamivudine [45]. SAR study is depicted
in Fig. 5.

Fig. 8. SAR of HCV NS5B polymerase inhibitors.

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Fig. 9. SAR of 2-phenyl benzimidazole derivatives for antiviral activity.

A new series of 2-phenyl benzimidazole derivatives was evalu- 30 -pyridyl and 40 -pyridyl at 2-position and oxadiazoles, thiadiazole,
ated for cytotoxicity and antiviral activity against ten RNA and DNA or triazole substituent at the 4 or 5-position were found to display
viruses. SAR study was performed as shown in Fig. 9. Amongst the activities against CVB3 and CVB6 as displayed in Fig. 10. Compound
series, compounds 10 and 11 were reported to have high activity 12 (IC50 ¼ 1.08 mM, SI ¼ 61.7 against CVB3) was found to be the most
[49]. promising candidate as lead compound for anti-enteroviral drug
Wubulikasimu et al. reported the synthesis of a series of novel [50].
benzimidazoles bearing a heterocyclic ring as oxadiazole, thiadia- Monforte et al. synthesized N-1-aryl-benzimidazoles 2-
zole, triazole and evaluated for their activities against Coxsackie substituted analogs and screened them as novel HIV-1 non-
virus B3 and B6 in Vero cells. Compounds with moieties 20 -pyridyl, nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the

Fig. 10. SAR of benzimidazole derivatives as anti-retrovirals.

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Fig. 11. SAR of benzimidazole analogs as NNRTIs.

compounds were effective in inhibiting the replication of human 15, 16, 17, 18 were found to constitute a better class of antitumor
immunodeficiency virus (HIV) at nanomolar concentration and also agents [52]. These compounds were found to act through a new
possessed low cytotoxicity. Among the series, compounds 13 and different mechanism that is cytosolic vacuolization and SAR study
14 surfaced out as the most promising candidates having potent was also carried out as shown in Fig. 12.
activity and as well as no toxicity [51]. SAR study was also carried Gowda et al. in 2009 prepared novel 1-(4-methoxyphenethyl)-
out to find the important functional groups that enhance the ac- 1H-benzimidazole-5-carboxylic acid derivatives and their biolog-
tivity are shown in Fig. 11. ical evaluation was performed for antileukemic activity. Among the
synthesized compounds, Compound 19(methyl 2-(4-fluoro-3-
nitrophenyl)-1H-benzimidazole-5-carboxylate) induced
3.2. Anticancer activity maximum cell death in leukemic cells with an IC50 value of 3 mM
[13]. SAR study is also depicted in Fig. 13.
Xiang et al. reported synthesis of novel benzimidazole de-
rivatives as potential antitumor agents. After the study, compounds

Fig. 12. SAR of antitumor agents.

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Fig. 13. SAR of 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives as antileukemic agents.

Fig. 14. SAR of novel antitumor benzimidazoles.

Fig. 15. SAR of 2-mercapto-1H-benzimidazole derivatives as anticancer agents.

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Fig. 16. SAR of 2-(phenyl)-3H-benzo[d]imidazole-5-carboxylic acids and its methyl esters as anti-breast cancer agents.

Fig. 17. SAR of benzimidazole derivatives as sirtuin inhibitors with antitumor activities.

Fig. 18. SAR of novel 1,2,3,4-tetrahydro[1,2,4]triazino[4,5-a]benzimidazole derivatives.

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Fig. 19. SAR of bisbenzimidazoles as novel inhibitors of topoisomerase l.

Omar et al. reported synthesis and docking studies of novel hydroxyl and 5-fluoro substitution in the aryl ring was found to
antitumor benzimidazole derivatives having allyl or ethylacetate be the most potent [55] as shown in Fig. 16.
group. Among these compounds, compounds 20 and 21 were found Yoon et al. carried out the synthesis and screening of novel
to be more potent in comparison to the standards [53] and their benzimidazole derivatives as sirtuin inhibitors (SIRT1 and SIRT2)
relation with activity was carried out through SAR study as shown with antitumor activities. All the compounds of the series displayed
in Fig. 14. better inhibition on SIRT2 in comparision to the SIRT1. Among
Liu et al. incorporated a hydrazone group into the 2-(phenyl- these, compound 26 displayed the good inhibitory activity on both
thiomethyl)-1H-benzo-[d]-imidazole and evaluated their biological SIRT1 (IC50 ¼ 58.43 mM) as well as for SIRT2 (IC50 ¼ 45.12 mM). In
activity against five cancer cells by the MTT assay. Among them two addition to that, cell cytotoxicity assays also showed good anti-
compounds 22 and 23 displayed excellent cancer inhibitory activity tumor activity against two different cancer cell lines MCF-7 and
in comparision with 5-FU and SU11248 [54]. SAR study was per- MDA-MB-468, derived from breast cancer [56]. SAR study was also
formed to get the relation between important functional groups done to know the contribution of different functional groups in
and their biological activity as displayed in Fig. 15. activity as shown in Fig. 17.
Karthikeyan et al. reported some 2-(phenyl)-3H-benzo[d]imid- Hala Bakr El-Nassan introduced a series of novel 1,2,3,4-
azole-5-carboxylic acids and its methyl esters as potent anti-breast tetrahydro[1,2,4]triazino[4,5-a]benzimidazoles carrying variety of
cancer agents. Among the carboxylic acid derivatives, compound 24 aryl and heteroaryl groups at position 1 and screened it for anti-
with 3, 4 dihydroxy substitutions in the aryl ring is the most active tumor activity human breast adenocarcinoma cell line (MCF7).
while among the methyl ester derivatives, compound 25 with 2- SAR study was carried out to establish a proper relationship

Fig. 20. SAR of 2-phenyl benzimidazoles as anthelmintics.

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Fig. 21. SAR of benzimidazole derivatives as cysticidal agent.

between structure and activity as shown in Fig. 18. Among the se- Gobis et al. introduced synthesis of cyclohexylethyl group con-
ries, compound 27 filtered out as a potent compound [57]. nected to the benzimidazole system or systems of benzimidazole
Singh and Tandon in 2011 reported synthesis of 2-aryl- type structure, as well as other heterocyclic rings and evaluated
substituted 2-bis-1H-benzimidazoles and evaluated them as their tuberculostatic activity against Mycobacterium tuberculosis
topoisomerase I inhibitors. Topoisomerase I inhibitors constitute a H37Rv, Spec. 192 and Spec. 210 strains, using the two-fold serial
novel family of antitumor agents. All the four compounds of the dilution MIC method as shown in Fig. 23. The results showed that
series as depicted in Fig. 19, showed a potent inhibitory effect on all compounds 33a, 33c, 33e and 33f bearing benzimidazole or
the cell lines, with IC50 in the mM range. Dihalogenated phenyl benzimidazole-like systems exhibit potent tuberculostatic activity
bearing derivatives 28a and 28b showed effective inhibition of the with low MIC value and compound 33a of 1a series specifically had
enzyme activity than the di and trimethoxyphenyl bearing com- no cytotoxic effect on the proliferation of neonatal human dermal
pounds 28c and 28d [58]. fibroblasts in vitro but also stimulated type I collagen output [61].

3.5. Antimicrobial activity

3.3. Anthelmintic activity

Zhou et al. in 2013 reported a series of 2-arylbenzimidazole

Sawant et al. in 2011 reported the synthesis and biological
derivatives as potential antioxidant and antimicrobial agents.
evaluation of some 2-phenyl benzimidazole-1-acetamides for
Compound 34 showed the highest HO scavenging activity
anthelmintic activity. Some of the compounds of the series were
(EC50 ¼ 46 mM) in vitro and others found to possess moderate
found to be more active to paralyze worms whereas others were
inhibitory activity against Staphylococcus aureus selectively at non-
more potent to cause death of worms in comparison to the stan-
cytotoxic concentrations [62]. SAR study is illustrated in Fig. 24.
dard albendazole. Amongst the series, compound 29 was the most
Joshi and Parikh reported in 2013, synthesis and evaluation of
potent to paralyze worms as well as to cause death of worms [59]
some benzimidazole derivatives as antimicrobial agents against
and reason is shown in Fig. 20, during the SAR study.
Staphlococcus aureus, Enterococcus fecalis, Pseudomonas aeruginosa,
Palomares-Alonso et al. reported synthesis and in vitro cysticidal
Candida albicans, Escherichia coli and Aspergillus niger. With the help
activity of new benzimidazole derivatives against Taenia crassiceps
of SAR study as shown in Fig. 25, it was clearly observed that the 35,
cysts. Compounds 30 and 31 exhibited good activity. Molecular
36, 37 derivatives with electron-withdrawing functional groups
modeling studies, revealed that the molecule should possess H
were found to be more active than electron-donating functional
group at 1-position, a methyl carbamate group at 2-position and an
groups [63].
orthogonal substituent at 5-position for cysticidal activity as shown
Jardosh et al. carried out synthesis of a new series of pyrido[1,2-
in Fig. 21 [24].
a]benzimidazole derivatives bearing the aryloxypyrazole nucleus
and evaluated them for antimicrobial activity as demonstrated in
3.4. Antimycobacterial activity Fig. 26. Majority of the compounds were found to be active against
the employed strains [64].
Yoon et al. reported the synthesis and screening of novel Garudachari et al. carried out synthesis of quinoline incorpo-
benzimidazole derivatives for antimycobacterial activity by using rated benzimidazole derivatives and screened them for in-vitro
agar dilution method. Among the screened compounds, 32 came antimicrobial and antifungal activities by well plate method.
out as the most active with MIC of 0.112 mM against MTB-H37Rv Among the screened compounds 38a, 38b, 39a and 39b showed
and 6.12 mM against INHR-MTB, respectively [60] shown in Fig. 22. excellent inhibition of bacterial growth. Compound 39b showed
430 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443

Fig. 22. SAR of benzimidazole derivatives as antimycobacterials.

significant inhibition of fungal strain [65]. SAR study is demon- 40h exhibited comparatively good activity against the tested bac-
strated in Fig. 27. terial and fungal strains but also displayed significant activity
Ranjith et al. reported the synthesis of derivatives of 5-bromo-1- against M. tuberculosis H37Rv strain [66].
[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimid- Zhang et al. synthesized a series of novel actinonin derivatives
azole,6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy) methyl]- containing a benzimidazole moiety linked as amide isostere and
1H-benzimidazole and 4-((5(6)-bromo-1H-benzoimidazol-2-l)- evaluated them in vitro against Staphylococcus aureus, Klebsiella
methoxy) benzenamine and the compounds were investigated for pneumoniae, and Sarcina lutea. Among these, compound 41 with
their antimicrobial and antimycobacterial activities and SAR study unsubstituted benzimidazole ring possessed potent antibacterial
was also carried out as shown in Fig. 28. Compounds 40b, 40e and activities especially high activity against K. pneumoniae. SAR studies

Fig. 23. SAR of 2-cyclohexylethylbenzimidazole derivatives as tuberculostatic agents.

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Fig. 24. SAR of 2-arylbenzimidazole derivatives as antioxidant and antimicrobial agents.

Fig. 25. SAR of 2-substituted benzimidazoles as antimicrobial agents.

revealed that the compounds with aliphatic substituents on the

benzene ring of the benzimidazole showed better result than those
with the amidation groups as shown in Fig. 29 [67].
€
Ozkay et al. synthesized novel benzimidazole compounds
bearing hydrazone moiety to discover their antibacterial and anti-
fungal activity. SAR study was also performed to search out the
possible connection between antibacterial activity and electronic
properties of the target compounds as demonstrated in Fig. 30 [68].
Seenaiah et al. reported some benzimidazole derivatives bearing
thio, methylthio and amino moieties as antimicrobials. Compound
42 surfaced out as the most potent antimicrobial against Staphy-
lococcus aureus (29 mm and 12.5 mM) and Penicillium chrysogenum
(38 mm and 12.5 mM) on evaluation with the parameters of zone of
inhibition and MIC values. SAR study was also performed which
indicated that the flexibility of methylthio moiety was mainly
responsible for the higher activity as summarized in Fig. 31 [69].
Some benzimidazole derivatives were reported as antimicro-
bials by incorporating alkyl chain as linker at N-1 position. Com-
Fig. 26. SAR of pyrido[1,2-a]benzimidazole derivatives of aryloxypyrazole.
pounds 43, 44 and 45 showed significant activity against
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Fig. 27. SAR of benzimidazole derivatives bearing quinoline ring as antimicrobial agent.

Staphylococcus aureus and Bacillus subtilis, Escherichia coli, Salmo- less than the standard drug ciprofloxacin. In case of fungal strains
nella typhi, Klebsiella pneumoniae and Pseudomonas aeruginosa but like Candida albicans and Aspergillus niger, most of the compounds

Fig. 28. SAR of 5 and 6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy) methyl]-1H-benzimidazole as antimicrobial and antitubercular agents.
 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443 433

Fig. 29. SAR of novel actinonin derivatives containing benzimidazole heterocycles as antimicrobials.

Fig. 30. SAR of benzimidazole derivatives bearing hydrazone moiety.

were found to exhibit potency comparable or more than that of 3.6. Anticonvulsant activity
standard drug fluconazole. Molecular docking study related to that
series was also previously reported [70]. A structure activity rela- Shingalapur et al. reported a series of benzimidazole derivatives,
tionship (SAR) was also carried out as displayed in Fig. 32 [71]. a group of 4-thiazolidinones and 1,3,4-oxadiazoles containing 2-

Fig. 31. SAR study of benzimidazole derivatives bearing thio, methylthio and amino moieties as antimicrobials.
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Fig. 32. SAR study of benzimidazole derivatives with N-1 alkyl linker.

mercapto benzimidazole moiety and screened them for in vivo Compound 46d cleaved DNA completely as no traces of DNA were
anticonvulsant activity. Compounds 46c, 46d, 46g and 46i were found while other compounds were seen to be nearly completely
considered to be significant compared to the control group for inactive to cleave DNA [72]. For the deep insight into the important
anticonvulsant activity. Meanwhile compounds 47c, 47d, 47h and functional groups contribution towards the activity, SAR study was
47i showed excellent activity against glibenclamide and were carried out as indicated in Fig. 33.
found to be significant compared to diabetic control group.

Fig. 33. SAR of 2-benzimidazole derivatives as anticonvulsants.

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Fig. 34. SAR of benzimidazole derivatives as analgesic and anti-inflammatory agents.

3.7. Analgesic and anti-inflammatory activity inflammatory (100% at 100 mg/kg b.w) activities in comparision to
the standard drug nimesulide (100% at 50 mg/kg b.w) respectively
Achar et al. reported the synthesis, screening of some benz- [73].
imidazole derivatives and on the basis of analgesic and anti- In 2013, El-Nezhawy et al. reported some novel benzimidazole
inflammatory activity of derivatives, SAR study was performed as derivatives having substituted pyrid-2-yl moiety and polyhydroxy
shown in Fig. 34. Amongst the series two compounds 48 and 49 sugar conjugated to the N-benzimidazole moiety and evaluated the
showed potent analgesic (89% at 100 mg/kg b.w) and anti- series for both anti-inflammatory and anti-ulcerogenic activity.

Fig. 35. SAR of benzimidazole derivatives with anti-inflammatory activity.

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Fig. 36. SAR of benzimidazole derivatives as glucokinase activators.

Compound 50 and 51 came out as the potent which displayed anti- discovery of a potent and metabolically stable compound 53(R)
inflammatory activities by the significant reduction of the inflam- [75].
mation in paw edema model but also showed significant anti- Kwak et al. reported synthesis of aminobenzimidazole de-
ulcerogenic activity. The potency of the compounds is attributed rivatives having a phenylcyclohexyl acetic acid group as depicted in
to the presence of the electron-donating methoxy groups in pyrid- Fig. 37 and evaluated them for anti-obesity and anti-diabetic ac-
2-yl moiety in both the compounds while presence of extra poly- tivity. Among the series, compound 54 showed in vitro activity for
hydroxy sugar linked to the N-benzimidazole moiety in compound human and mouse DGAT-1(diacylglycerol acyl transfrase) but good
51 results in anti-inflammatory as well as remarkable anti-ulcer selectivity toward DGAT-2, excellent human liver metabolic sta-
activity in comparision to the compound 50 as illustrated in bility, PK and safety profiles including hERG, CYP inhibition, in-
Fig. 35 [74]. duction, and acute toxicity [76].

3.9. Antiprotozoal activity

3.8. Anti-diabetic activity
Valdez-Padilla et al. reported the synthesis and in vitro anti-
Ishikawa et al. in 2009 carried out the synthesis of 2-(pyridine- protozoal activity of 1-methyl benzimidazoles substituted at posi-
2-yl)-1H-benzimidazole and also performed structureeactivity- tion 2 with esters and amides as shown in Fig. 38. Results clearly
relationships (SARs) study on glucokinase activators (GKAs) as indicated that ester derivatives of carboxylic acids are more active
displayed in Fig. 36. Compound 52 surfaced out as an attractive than amide derivatives against both the parasites Giardia intesti-
molecule for further modification to improve GK potency and to nalis and Trichomonas vaginalis. The most active compounds were
develop further structurally diverse GKAs. Compound 52 led to the 55, 56, 57 and 58 with a 2-ethoxycarbonyl group in common and

Fig. 37. SAR of aminobenzimidazole derivatives containing phenylcyclohexyl acetic acid group.
 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443 437

Fig. 38. SAR of benzimidazole derivatives as antiprotozoal agents.

Fig. 39. SAR of benzimidazole derivatives as antiplasmodial agents.

Fig. 40. SAR exploration using activity landscape modeling with a systematic pairwise comparison of the R groups of all molecular pairs against Trichomonas vaginalis and Giardia
intestinalis.
438 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443

Fig. 41. SAR study of 2-{[2-(1H-imidazol-1-yl) ethyl]sulfanyl}-1H-benzimidazole derivatives as antiprotozoal agents.

Fig. 42. SAR of benzimidazole derivatives as ADAMTS-5 inhibitors.

were also independent of the substitution pattern at the benzenoid acetophenone moiety in compound 60 as shown in Fig. 39, were
ring [77]. crucial for antiplasmodial activity [78].
Saify et al. reported a series of benzimidazole derivatives as Aguayo-Ortiz et al. subjected 91 compounds with reported ac-
inhibitors of intraerythrocytic Plasmodium falciparum plasmepsin II tivity against Trichomonas vaginalis and Giardia intestinalis to an
in culture and found that the substitution of a phenyl group in initial SAR exploration using activity landscape modeling with a
compound 59 and a chlorine atom at the para position of the systematic pairwise comparison of the R groups of all molecular

Fig. 43. SAR of benzimidazole derivatives as phosphodiesterase 10A inhibitors.

 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443 439

Fig. 44. SAR of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butylcholinesterase.

pairs. This modeling method compares systematic changes in the 3.11. Antipsychotic activity
substitutions of the analog series and finds the co-relation between
these changes and response in biological activity as shown in Hamaguchi et al. carried out the synthesis and evaluation of
Fig. 40. This SAR study helps in the design of new and more se- novel benzimidazoles as phosphodiesterase 10A inhibitors but with
lective benzimidazole derivatives with antiprotozoal activity [79]. reduced CYP1A2 inhibition. Among the series, compound 62 sur-
A new series of 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H- faced out as the potent PDE10A (phosphodiesterases) inhibition
benzimidazole derivatives was reported to be active against Tri- with reduced CYP1A2 (cytochrome P450 1A2) inhibitory because of
chomonas vaginalis, Giardia intestinalis and Entamoeba histolytica the introduction of an isopropyl group at the 2-position and a
with IC50 values in the nanomolar range, which were more than methoxy group at the 5-position of the benzimidazole ring as
that of the standard drug metronidazole. SAR study was also carried illustrated in Fig. 43 [82].
out as illustrated in Fig. 41 [80]. Zhu et al. reported synthesis of a series of novel 2-
aminobenzimidazole derivatives under microwave irradiation and
3.10. ADAMTS-5 (AGGRECANASE-2) inhibitors evaluated them for acetylcholinesterase (AChE) and butyr-
ylcholinesterase (BuChE) inhibition. Among the series, compounds
Sogame et al. reported a series of benzimidazoles bearing the 63 and 64 were found to be active and molecular modeling study
thiazolidin-4-one as ADAMTS-5 A (aggrecanase-2) inhibitors. was also performed on them to find out the mechanism of action on
Amongst the series, compound 61 came out as a potent ADAMTS-5 the two enzymes inhibition. Compounds were found to form a
inhibitor with good permeability and this is also proved with the hydrogen bond with His438 at the catalytic site of BuChE and also
help of SAR study as demonstrated in Fig. 42 [81]. fits well into the hydrophobic pocket formed by Ala328, Trp430 and

Fig. 45. SAR of potent NPY Y5 receptor antagonists.

440 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443

Fig. 46. SAR study of bis benzoxazolyl/benzothiazolyl/benzimidazolyl pyrazoles/isoxazoles/pyrimidines.

Tyr332 of BuChE. Benzimidazoles were not able to access the nar- antioxidant activity. Benzoxazolyl amido-linked derivatives dis-
rower active site of AChE due to the protruding regions of Phe330 played greater radical scavenging activity than the benzothiazolyl
and Phe331 in AChE and was the reason for the higher selectivity of and benzimidazolyl amido-linked derivatives and is shown during
compounds 63, 64 for BuChE over AChE as illustrated in Fig. 44 [83]. SAR study in Fig. 47 [86].
Tamura et al. in 2012 reported the synthesis of some novel Padmavathi et al. reported a series of novel heterocycles such as
benzimidazole derivatives and evaluated them as highly potent bis benzoxazolyl/benzothiazolyl/benzimidazolyl pyrazoles/iso-
NPY Y5 receptor antagonists. Substitution at the 2-position with xazoles/pyrimidines and evaluated their antioxidant activity using
pyridine moiety gave potent analogs 65a, 65b and 65c having many three methods such as 2,2,-diphenyl-1-picrylhydrazyl (DPPH)
0
characteristics like low to sub-nanomolar Y5 receptor binding af- method, nitric oxide (NO) method and 2,2 -azino-bis(3-
finities, improved CYP450 inhibition profiles, good solubilities and ethylbenzthiazoline-6-sulfonic acid)ABTS method. Amongst the
high metabolic stabilities as demonstrated in Fig. 45 [84]. series, compound 66 exhibited good antioxidant activity in com-
parison to the standard ascorbic acid. SAR study showing the effect
of moieties on activity is depicted in Fig. 48 [87].
3.12. Antioxidant activity

Padmavathi et al. reported some bis benzoxazolyl/benzothia- 4. Conclusion

zolyl/benzimidazolylepyrazoles/isoxazoles/pyrimidines synthe-
sized from ketene dithiolates and evaluated their antioxidant Benzimidazoles have revolutionized medicinal chemistry by
property. Compounds having pyrazolyl and isoxazolyl units in their diverse biological activities which make them a beneficial
combination with bis benzoxazole ring showed excellent radical scaffold and act via various mechanisms in treatment of several
scavenging activity when compared with the standard ascorbic diseases. Their antagonistic effect makes them potential candidates
acid. Conversely, benzimidazole derivatives possessed least activity. for the synthesis of various potent and efficacious molecules. A
SAR study is annotated in Fig. 46 [85]. number of drugs like albendazole, mebendazole, thiabendazole as
Durgamma et al. reported some amido-linked benzoxazolyl/ antihelmintics; omeprazole, lansoprazole, pantoprazole as proton
benzothiazolyl/benzimidazolyl-pyrroles and benzoxazolyl/ pump inhibitors; astemizole as antihistaminic; enviradine as anti-
benzothiazolyl/benzimidazolyl-pyrazoles and evaluated for their viral; candesarten cilexitil and telmisartan as antihypertensives

Fig. 47. SAR study of amido-linked benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrroles and benzoxazolyl/benzothiazolyl/benzimidazolyl-pyrazoles as antioxidant agents.
 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443 441

Fig. 48. SAR study of novel heterocycles such as bisbenzoxazolyl/benzothiazolyl/benzimidazolyl pyrazoles/isoxazoles/pyrimidines as antioxidants.

Fig. 49. Summary of structural modifications of benzimidazole to influence the activity.

442 G. Yadav, S. Ganguly / European Journal of Medicinal Chemistry 97 (2015) 419e443

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