European Journal of Medicinal Chemistry 126 (2017) 705e753

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

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

Review article

Therapeutic evolution of benzimidazole derivatives in the last

quinquennial period
Wasim Akhtar a, Mohemmed Faraz Khan a, Garima Verma a, M. Shaquiquzzaman a,
M.A. Rizvi b, Syed Hassan Mehdi b, Mymoona Akhter a, M. Mumtaz Alam a, *
a
Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
b
Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India

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

Article history: Benzimidazole, a fused heterocycle bearing benzene and imidazole has gained considerable attention in
Received 30 September 2016 the eld of contemporary medicinal chemistry. The moiety is of substantial importance because of its
Received in revised form wide array of pharmacological activities. This nitrogen containing heterocycle is a part of a number of
10 November 2016
therapeutically used agents. Moreover, a number of patents concerning this moiety in the last few years
Accepted 3 December 2016
further highlight its worth. The present review covers the recent work published by scientists across the
Available online 5 December 2016
globe during last ve years.
2016 Elsevier Masson SAS. All rights reserved.
Keywords:
Heterocyclic
Benzimidazole
Biological activity
Anti-inammatory and analgesic
Anti-cancer
Antiviral

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
2. Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
2.1. Anti-cancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
2.2. Anti-inflammatory and analgesic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
2.3. Anti-microbial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
2.4. Neuro-protective agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
2.5. Anti-hypertensive agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
2.6. Antiviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
2.7. Anti-tubercular activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
2.8. Anti-protozoal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
2.9. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746

1. Introduction

The chemistry of benzimidazole (Fig. 1) has been an interesting

eld of study since decade. Benzimidazole is a moiety that contains
benzene and a heterocyclic imidazole ring. It is one of the most
* Corresponding author.
promising moieties that is present in many clinically useful drugs
E-mail address: drmmalam@gmail.com (M.M. Alam).

http://dx.doi.org/10.1016/j.ejmech.2016.12.010
0223-5234/ 2016 Elsevier Masson SAS. All rights reserved.
706 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Abbreviations M. luteus Micrococcus luteus

K. planticola Klebsiella planticola
CXCR3 Chemokine receptor A. niger Aspergillus niger
ITK Interleukin 2-inducible T cell kinase P. chrysogenum Penicilliu;m chrysogenum
Lck Lymphocyte tyrosine kinase C.utilis Candida utilis
IC50 Half maximal inhibitory concentration S. maltophilia Stenotrophomonas maltophilia
mM Micromolar K. pneumoniae Klebsiella pneumoniae
GI50 Growth Inhibition A. avus Aspergillus avus
FGFR1 Fibroblast growth factor receptor 1 E. faecium
rhCK2a Human recombinant casein kinase 2 alpha Enterococcus faecalis
MEK1 Mitogen-activated protein kinase M. tuberculosis Mycobacterium tuberculosis
PI3K Phosphatidylinositol 3-kinase M. bovis Mycobacterium bovis
nM Nanomolar T. vaginalis Trichomonas vaginalis
EGFR Epidermal growth factor receptor G. intestinalis Giardia intestinalis/*
ADP-ribose Adenosine diphosphate ribose E. histolytica Entamoeba histolytica
DHODH Dihydroorotate dehydrogenase L. donovani Leishmania donovani
DNMT3A DNA (Cytosine-5-)-methyltransferase 3 alpha T. cruzi Trypanosoma cruzi
PBMC Peripheral blood mononuclear cell MCH Melanin-concentrating hormone
VEGFR Vascular endothelial growth factor receptor AD Alzheimer's disease
Chk1 Checkpoint kinase1 Ach Acetylcholine
hTERT Human telomerase reverse transcriptase Ab Amyloid-b-peptide
LDH Lactate dehydrogenase CRF1 receptor Corticotropin-releasing hormone receptor 1
CRTH2 Chemoattractant receptor homologous to the T helper mGluR5 Metabotropic glutamate receptor 5
2 hPreP Presequence protease
JAK Janus kinase AChE Acetylcholinesterase
MIC Minimum inhibitory concentration BuChE Butyrylcholinesterase
S. aureus Staphylococcus aureus PKd Polycystic kidney disease
E. coli Escherichia coli NPY Neuropeptide Y
S. typhi Salmonella typhi NMDA N-methyl-D-aspartate
E. faecalisEnterococcus faecalis ICH Intracerebral hemorrhage
P. aeruginosa Pseudomonas aeruginosa BP Blood pressure
C. albicans Candida albicans HAV Hepatitis A virus
C. tropicalis Candida tropicalis TB Tuberculosis
S. cerevisae Saccharomyces cerevisiae DOTS Directly observed therapy short-course
B. proteus MCHR Melanin-concentrating hormone receptor
Bacillus proteus hCB2R Human cannabinoid receptor type 2
B. subtilis Bacillus subtilis PDE10A Phosphodiesterase 10A
S. pneumoniae Streptococcus pneumoniae T2DM Type 2 Diabetes mellitus
S. pyogenes Streptococcus pyogenes CK1 g Casein kinase 1 gamma
M. catarrhalis Moraxella catarrhalis SPR Surface plasmon resonance
S. abony Salmonella abony JNK3 kinase Jun amino-terminal kinase
F. tularensis Francisella tularensis

anti-hypertensive [10], H3 antagonistic [11], human glucagon re-

Fig. 1. Structure of benzimidazole.
[1]. Its derivatives are of wide interest because of their various
biological activities and clinical applications [2]. Benzimidazole
moiety fullls the minimum structural requirements that are
common for anti-inammatory compounds [3,4]. It has been re-
ported that many molecules containing benzimidazole moiety have
signicant anti-inammatory as well as analgesic activity [5]. Sci-
entists from worldwide have reported remarkable activity against
fungi and bacteria [6]. In addition, the benzimidazole-substituted
compounds have antiviral [7], anthelmintic, antiproliferative [8,9],
ceptor antagonistic [12], male contraceptive [13] and anti-infective
[14] activities. These molecules also inhibit chemokine receptor
(CXCR3) [15], interleukin 2-inducible T cell kinase (ITK) [16] and
lymphocyte tyrosine kinase (Lck) [17]. 1-H Benzimidazole and its
simple derivatives have also been claimed to prevent stomach
damage caused by inammation inhibitors [18]. N-containing
benzimidazole derivatives have well known biological activities
such as proton pump inhibitor (Omeprazole) [19], antihelminthic
(Albendazole) [20], antidopaminergic (Domperidone) [21] and
antipsychotic (Pimozide).
This moiety can be traced in a number of well established drugs
belonging to different categories with diverse therapeutic activities.
Such drugs are enlisted in Table 1.
Numerous patents published on this moiety are given in Table 2.
2. Pharmacological activities
Owing to the diverse pharmacological activities of this ring, a
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 707

Table 1
Benzimidazole bearing Pharmacological Agents.

S.No. Name of the drug Structure Pharmacological class

1. Omeprazole Proton pump inhibitor [22]

2. pantoprazol Proton pump inhibitor [22]

3. Triclabendazole Anthelmintic drugs [23]

4. Benomyl Fungicide [24]

5. Carbendazim Fungicide [24]

6. Fuberidazole Fungicide [24]

7. Thiabendazole Anthelmintic drug [24]

8. Candesertan Anti-hypertensive [25]

9. Mebendazole Worm infestation [26]

(continued on next page)

708 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Table 1 (continued )

S.No. Name of the drug Structure Pharmacological class

10. Astemizole Antihistamine [27]

11. Albendazole Anthelmintic drug [28]

12. Bendamustine Anti-cancer [29]

13. Rabeprazole Anti-ulcer [30]

14. Telmisartan Anti-hypertensive [31]

number of researchers across the globe are working on design and
development of benzimidazole based derivatives. Recent de-
velopments made by researchers during last ve years in this eld
are discussed in the following sections.
2.1. Anti-cancer activity
Cancer is a complex class of diseases in which a group of cells
exhibit uncontrolled growth of cell and sometimes metastasis. It is
a vital public health problem and remains second major cause of
death worldwide [93e95]. Currently, there are different type of
approaches to identify cancer cells, such as electrochemical
methods [96], biosensors [97], immunocyto chemistry [98] and
microuidic devices [99]. There are several classes of compounds
used for the treatment of this deadly disease. Amongst different
known moieties, benzimidazole based compounds are known to
have signicant cytotoxic effect. Several benzimidazole based anti-
proliferative compounds have been developed by researchers
(Fig. 2) during last ve years.
Benzimidazole substituted derivatives developed by Sharma
et al. were evaluated for their in vitro cytotoxic activity against
human cancer cell lines. Among the tested compounds, compound
1 showed signicant activity against MDA-MB-231 and 4T1 cancer
cells with half maximal inhibitory concentration (IC50) values of
3.26 0.24 mM and 5.96 0.67 mM respectively [100]. Singla et al.
synthesized a series of triazine-benzimidazole analogues and
evaluated them for their in vitro anti-cancer activitiy. Following
evaluation, compounds 2a, 2b, 2c and 2d were reported as the most
active compounds of the series with half maximal growth inhibi-
tory concentration (Gl50) of 2.68 mM, 1.38 mM, 2.37 mM and 0.72 mM
respectively. The structure-activity relationship (SAR) described
that hybrids with heterocyclic hydrophobic groups are benecial
for anticancer activity [101]. Wu et al. synthesized a series of
benzimidazole-2-subsituted phenyl or pyridine propyl ketene de-
rivatives and assayed them for in vitro growth-inhibitory activity
against HCT116, MCF-7 and HepG2 cell lines. Compounds 3a and 3b
were reported to be the most active with an IC50 value in the range
of 0.06e3.64 mM and 0.04e9.80 mM, respectively. SAR studies
describe that the 3-Cl substitution on the phenyl ring exhibited the
best inhibitory activity. Compound obtained on replacing the
phenyl group by a 2-pyridine ring also showed high inhibitory ac-
tivity. However, replacing the phenyl ring with a 3- or 4-pyridine
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 709

Table 2
Patents of benzimidazole.

S.no. Patent no. Patent date Inventors Description

1. US 20150361032 A1 17 Dec, 2015 Hassan Pajouhesh, Richard Holland, Lingyun Zhang, Hossein The patent describes Benzimidazole inhibitors of
[32] Pajouhesh, Jason Lamontagne, Brendan Whelan the sodium channel.
2. US 20150360147 A1 [33] 17 Dec, 2015 Gordon R. Dufn, Victoria Jane Dolan, Katherine Louise The patent describes Benzimidazole compounds
Angus, Andrew Lyddiatt and their use as chromatographic ligands.
3. US 20150352121 A1 [34] 10 Dec, 2015 Kurtis Earl Bachman, Joel David Greshock, Mary Ann The patent describes inhibition of PI3K-b and/or B-
Hardwicke Raf is benecial, eg. cancer.
4. US 20150336967 A1 [35] 26 Nov, 2015 Wojciech Czardybon, Krako


w BrzOzka, Michal Galezowski, The patent describes Novel benzimidazole
Renata Windak, Mariusz Milik, Magdalena Zawadzka, Pawel derivatives as kinase inhibitors.
Guzik, Ewelina Wincza, Marta Prokop, Katarzyna Wiklik,
Aleksandra Sabiniarz, Wieslaw Marek Cholody, Raymond
Horvath, Tomasz Rzymski
5. US 20150329527 A1 [36] 19 Nov, 2015 Ahmed Kamal, Anver Basha Shaik, Gajjela Bharath Kumar, The patent describes Pyrazole linked benzimidazole
Vangala Santhosh Reddy conjugates and a process for preparation.
6. US 20150322073 A1 [37] 12 Nov, 2015 Harald Engelhardt The patent describes benzimidazole derivative as
abnormal cell proliferation.
7. US 20150322066 A1 [38] 12 Nov, 2015 Nobuyuki Tanaka, Kenji Yamawaki, Jiangchao Yao, Jianming The patent describes substituted benzimidazole-
Yu, Xiaoming Zhou Type piperidine Compound, and methods to treat or
prevent a condition, such as pain.
8. US 20150322065 A1 [39] 12 Nov, 2015 Thomas Allen Chappie, Patrick Robert Verhoest, Nandini The patent describes azabenzimidazole compounds
Chaturbhai Patel, Matthew Merrill Hayward for treating certain central nervous system (CNS),
metabolic, autoimmune and inammatory diseases
or disorders.
9. US 20150311555 A1 [40] 29 Oct, 2015 Hyoung-juhn Kim, Jin Young Kim, Sung Jong Yoo, Jong Hyun The patent describes the Dibenzylated
Jang, Eun Ae Cho, Sun-hee Choi, Jonghee Han, Hyung Chul polybenzimidazole based polymer.
Ham, Dirk Henkensmeier
10. US 20150307479 A1 [41] 29 Oct, 2015 Scott D. Kuduk, Casey C. Mccomas, Thomas S. Reger The patent describes Cyclobutyl benzimidazoles as
PDE10 inhibitors.
11. US 20150295189 A1 [42] 15 Oct, 2015 Jason Brooks, Geza Szigethy, Scott Beers, Hsiao-fan Chen The patent describes benzimidazole use as emitters
and devices, such as organic light emitting diodes
12. US 20150284411 A1 [43] 08 Oct, 2015 James M. Apgar, Ashok Arasappan, Tesfaye Biftu, Ping Chen, The patent describes Novel azabenzimidazole
Danqing Feng, Erin Guidry, Jacqueline D. Hicks, Ahmet hexahydrofuro[e,2-b]furan derivatives.
Kekec, Kenneth J. Leavitt, Bing Li, Troy Mccracken, Iyassu
Sebhat, Xiaoxia Qian, Lan Wei, Robert R. Wilkening, Zhicai
Wu
13. US 20150274726 A1 [44] 08 Oct, 2015 Tomasz Rzymski, Adrian Zarebski, Agnieszka Dreas, The patent describes Substituted tricyclic
Karolina Osowska, Katarzyna Kucwaj, Joanna Fogt, Marek benzimidazoles as kinase inhibitors.
Cholody, Michal Galezowski, Wojciech Czardybon,
Raymond Horvath, Katarzyna Wiklik, Mariusz Milik,

zka
Krzysztof Brzo
14. US 20150266827 A1 [45] 24 Sep, 2015 Laurence Rahme, Francois Lepine, Melissa Starkey, Biliana The patent describes Antibiotic tolerance inhibitors
Lesic-arsic
15. US 20150266739 A1 [46] 24 Sep, 2015 Aruna Zhamu, Bor Z. Jang The patent describes Production process for highly
conductive graphitic lms
16. US 20150265625 A1 [47] 24 Sep, 2015 S. David Brown, David J. Matthews The patent describes benzimidazole use as agents or
drugs for treating proliferative diseases.
17. US 20150258068 A1 [48] 17 Sep, 2015 Daniel P. Gold, Guillermo Garcia-manero The patent describes benzimidazole used as
Combination therapies.
18. US 20150252189 A1 [49] 10 Sep, 2015 Yi-feng Wang, Tim Hsu, Allan S. Hay, Kun Li, Bhavin N. Patel The patent describes benzimidazole improved high
temperature load capability and improved high
temperature melt processibility.
19. US 20150246889 A1 [50] 03 Sep, 2015 Junya Qu, Ralph A. Rivero, Robert Sanchez, Rosanna Tedesco The patent describes Benzimidazole derivatives as
pi3 kinase inhibitors.
20. US 20150246052 A1 [51] 03 Sep, 2015 Wenying Chai, Charlotte Deckhut, Curt A. Dvorak, Wendy The patent describes 1,2,5-substituted
Eccles, James P. Edwards, Steven D. Goldberg, Paul J. benzimidazoles as ap modulators
Krawczuk, Alec D. Lebsack, Jing Liu, Virginia M. Tanis, Kyle T.
Tarantino
21. US 20150225412 A1 [52] 13 Aug, 2015 Kenneth Albert Brameld, Timothy Owens The patent describes Benzimidazole derivatives as
itk inhibitors.
22. US 20150218183 A1 [53] 06 Aug, 2015 James M. Apgar, Ashok Arasappan, Tesfaye Biftu, Ping Chen, The patent describes Novel benzimidazole
Danqing Feng, Erin Guidry, Jacqueline Hicks, Ahmet Kekec, hexahydrofuro [3,2-b]furan derivatives.
Kenneth J. Leavitt, Bing Li, Iyassu Sebhat, Xiaoxia Qian, Lan
Wei, Robert R. Wilkening, Zhicai Wu
23. US 20150218149 A1 [54] 06 Aug, 2015 James M. Apgar, Tesfaye Biftu, Ping Chen, Danqing Feng, The patent describes Novel benzimidazole
Jacqueline D. Hicks, Ahmet Kekec, Kenneth J. Leavitt, Bing Li, tetrahydrofuran derivatives.
Iyassu Sebhat, Xiaoxia Qian, Lan Wei, Robert R. Wilkening,
Zhicai Wu
24. US 20150216168 A1 [55] 06 Aug, 2015 Jens Frackenpohl, Ines Heinemann, Thomas Mller, Jan The patent describes Use of substituted 2-
Dittgen, Pascal Von Koskull-do ring, Dirk Schmutzler, Martin amidobenzimidazoles active substances against
Jeffrey Hills abiotic plant stress.
25. US 20150210685 A1 [56] 30 July, 2015 James M. Apgar, Tesfaye Biftu, Ping Chen, Danqing Feng, The patent describes Novel azabenzimidazole
Jacqueline D. Hicks, Ahmet Kekec, Kenneth J. Leavitt, Bing Li, tetrahydropyran derivatives.
Iyassu Sebhat, Xiaoxia Qian, Lan Wei, Robert R. Wilkening,
Zhicai Wu
(continued on next page)
710 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Table 2 (continued )

S.no. Patent no. Patent date Inventors Description

26. US 20150209348 A1 [57] 30 July, 2015 Spyridon Chalkiadakis, Virginia Calder The patent describes Histamine 4 receptor partial
agonists, inverse agonists or antagonists for use in
treating non-autoimmune uveitis
27. US 20150209259 A1 [58] 30 July, 2015 Tatjana Schade, Kerstin Skubsch, Sina Brinkmann, Andreas The patent describes Octocrylene-free sunscreen
Bleckmann, David Schlenker composition with low stickiness
28. US 20150207083 A1 [59] 23 July, 2015 Thomas Schaefer, Flavio Luiz Benedito, Ute Heinemeyer, The patent describes Benzimidazo [1,2-a]
Nicolle Langer, Heinz Wolleb, Teresa Figueira Duarte, Soichi benzimidazole derivatives for electronic
Watanabe, Christian Lennartz, Gerhard Wagenblast, application.
Annemarie Wolleb, Kristina Bardon
29. US 20150203487 A1 [60] 23 July, 2015 James M. Apgar, Tesfaye Biftu, Ping Chen, Danqing Feng, The patent describes Novel azabenzimidazole
Jacqueline D. Hicks, Ahmet Kekec, Kenneth J. Leavitt, Bing Li, tetrahydrofuran derivativesuseful in the treatment
Iyassu Sebhat, Xiaoxia Qian, Lan Wei, Robert R. Wilkening, of Type 2 diabetes, hyperglycemia, metabolic
Zhicai Wu, Ashok Arasappan syndrome, obesity, hypercholesterolemia, and
hypertension.
30. US 20150203472 A1 [61] 23 July, 2015 Simona M. Ceccarelli, Ravi Jagasia, Roland Jakob-roetne, The patent describes Benzimidazoles as CNS active
Juergen Wichmann agents.
31. US 20150203455 A1 [62] 23 July, 2015 Christel Jeanne Marie Menet, Oscar Mammoliti, Javier Blanc, The patent describes Novel compounds and
Mislav Orsulic, Maja Roscic pharmaceutical compositions thereof for the
treatment of inammatory disorders.
32. US 20150197516 A1 [63] 16 July, 2015 James M. Apgar, Tesfaye Biftu, Ping Chen, Danqing Feng, The patent describes Novel benzimidazole
Jacqueline D. Hicks, Ahmet Kekec, Kenneth J. Leavitt, Bing Li, tetrahydropyran derivativesuseful in the treatment
Iyassu Sebhat, Xiaoxia Qian, Lan Wei, Robert R. Wilkening, of Type 2 diabetes, hyperglycemia.
Zhicai Wu
33. US 20150197497 A1 [64] 16 July, 2015 Chandima Abeywickrama, James E. Bradner, Shashikanth The patent describes Selective inhibitors of histone
Ponnala deacetylase isoform 6 and methods thereof.
34. US 20150196559 A1 [65] 16 July, 2015 Tong Wang, Stephen Gately The patent describes Compounds, pharmaceutical
compositions and methods of use of hydroxamic
acid derivatives.
35. US 20150183993 A1 [66] 02 July, 2015 Keki Hormusji Gharda, Prakash D. Trivedi, Tushar R. Parida, The patent describes Method for processing a high
Amitkumar Biradar temperature resistant thermosetting material.
36. US 20150183761 A1 [67] 02 July, 2015 Robert Murray Mckinnell, Lan Jiang, Daniel D. Long The patent describes Benzimidazole-carboxamide
compounds as 5-ht4 receptor agonists.
37. US 20150175608 A1 [68] 25 Jun, 2015 Abdellah Tahri, Tim Hugo Maria Jonckers, Pierre Jean-marie The patent describes Novel 4-substituted 1,3-
Bernard Raboisson, Sandrine Marie Helen Vendeville, Lili Hu dihydro-2h-benzimidazol-2-one derivatives
substituted with benzimidazoles as respiratory
syncytial virus antiviral agents.
38. US 20150175600 A1 [69] 25 Jun, 2015 Stephen John Atkinson, Michael David Barker, Matthew The patent describes 2-(azaindol-2-yl)
Campbell, Hawa Diallo, Clement Douault, Neil Stuart Garton, benzimidazoles as PAD4 inhibitors.
John Liddle, Robert John Sheppard, Ann Louise Walker,
Christopher Wellaway, David Matthew Wilson
39. US 20150171344 A1 [70] 18 Jun, 2015 Hyung Chan Bae, Young Mi Beak, Tae Hyung Kim, Ho Cheol The patent describes Novel compound and
Park, Chang Jun Lee, Jin Young Shin electroluminescent device including same.
40. US 20150168415 A1 [71] 18 Jun, 2015 Wen-bin Yang The patent describes Compounds and methods for
analysis and synthesis of saccharide compounds.
41. US 20150166533 A1 [72] 18 Jun, 2015 Abdellah Tahri, Tim Hugo Maria Jonckers, Pierre Jean-marie The patent describes Novel 1,3-dihydro-2h-
Bernard Raboisson, Sandrine Marie Helene Vendeville, benzimidazol-2-one derivatives substituted with
Ludwig Paul Cooymans, Samuel Dominique Demin benzimidazoles as respiratory syncytial virus
antiviral agents.
42. US 20150166527 A1 [73] 18 Jun, 2015 Christoph Boss, Christine Brotschi, Markus Gude, Bibia The patent describes Benzimidazole-proline
Heidmann, Thierry Sifferlen, Jodi Williams derivatives their use as orexin receptor antagonists.
43. US 20150166485 A1 [74] 18 Jun, 2015 Charles Q. Meng The patent describes Parasiticidal compositions
comprising benzimidazole derivatives, methods
and uses thereof.
44. US 20150164817 A1 [75] 18 Jun, 2015 Pawan Seth, Benoit Schmitt The patent describes Composition comprising a
benzimidazole and process for its manufacture.
45. US 20150158878 A1 [76] 11 Jun, 2015 Johann Leban, Mirko Zaja The patent describes Biuorodioxalane-amino-
benzimidazole kinase inhibitors for the treatment of
cancer, autoimmune inammation and CNS
disorders.
46. US 20150157652 A1 [77] 11 Jun, 2015 Gary Gordon The patent describes Veliparib in combination with
carboplatin for the treatment of triple negative
breast cancer.
47. US 20150157608 A1 [78] 11 Jun, 2015 Dizhong Chen, Hong Yan Song, Eric T. Sun, Niefang Yu, Yong The patent describes Benzimidazole derivatives:
Zou preparation and pharmaceutical applications.
48. US 20150152065 A1 [79] 04 Jun, 2015 Daniel Christopher Brookings, Mark Daniel Calmiano, Ellen The patent describes Tnf -alpha modulating
Olivia Gallimore, Helen Tracey Horsley, Martin Clive benzimidazoles.
Hutchings, James Andrew Johnson, Boris Kroeplien, Fabien
Claude Lecomte, Martin Alexander Lowe, Timothy John
Norman, John Robert Porter, Joanna Rachel Quincey, James
Thomas Reuberson, Matthew Duncan Selby, Michael Alan
Shaw, Zhaoning Zhu, Anne Marie Foley
49. US 20150150882 A1 [80] 04 Jun, 2015 Mark J. Macielag, Mingde Xia, Xiaoqing Xu The patent describes Benzimidazole derivatives
useful trpm8 channel modulators.
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 711

Table 2 (continued )

S.no. Patent no. Patent date Inventors Description

50. US 20150148392 A1 [81] 28 May, 2015 Lawrence Kolaczkowski The patent describes 2-((r)-2-methylpyrrolidin-2-
yl)-1h-benzimidazole-4-carboxamide crystalline
form 1.
51. US 20150141464 A1 [82] 21 May, 2015 Theodore Mark Kamenecka, Patrick R. Grifn, Amy S. Ripka, The patent describes N-biphenylmethyl
Jeffrey O. Saunders benzimidazole modulators of pparg
52. US 20150133516 A1 [83] 14 May, 2015 Brian K. Adams, Ed Schutter The patent describes Methods and compositions for
treating ADHD.
53. US 20150133500 A1 [84] 14 May, 2015 Laykea Tafesse, Jiangchao Yao, Xiaoming Zhou The patent describes Benzimidazole derivatives as
sodium channel blockers.
54. US 20150132661 A1 [85] 14 May, 2015 Zhongwei Chen, Michael Fowler, Hadis Zarrin The patent describes Highly ion-conductive nano-
engineered porous electrolytic composite
membrane for alkaline electrochemical energy
systems.
55. US 20150119533 A1 [86] 30 Apr, 2015 Kiu-seung Lee The patent describes Film comprising a mixture of
poly (m-phenylene isophthalamide) and copolymer
made from (6)-amino-2-(p-aminophenyl)
benzimidazole.
56. US 20150119511 A1 [87] 30 Apr, 2015 Kiu-seung Lee The patent describes Composite polymer solution of
poly(m-phenylene isophthalamide) and copolymer
made from (6)-amino-2-(p-aminophenyl)
benzimidazole.
57. US 20150119393 A1 [88] 30 Apr, 2015 Holger Wagner, Frank Himmelsbach The patent describes New azabenzimidazole
derivatives as metabolic diseases, in particular
diabetes type 2.
58. US 20150119382 A1 [89] 30 Apr, 2015 Wenying Chai, Curt A. Dvorak, Wendy Eccles, James P. The patent describes 1,2,6-substituted
Edwards, Steven D. Goldberg, Paul J. Krawczuk, Alec D. benzimidazoles as ap modulators.
Lebsack, Jing Liu, Daniel J. Pippel, Zachary S. Sales, Virginia
M. Tanis, Mark S. Tichenor, John J. M. Wiener
59. WO2014202763 A1 [90] 24 Dec, 2014 Alain Moussy, Abdellah Benjahad, Claire SCHALON, Didier The patent describes Benzimidazole derivatives as
Pez, Emmanuel Chevenier, Franck Sandrinelli, Jason Martin, selective proteine kinase inhibitors.
Willy Picoul, Less
60. US8372987 B2 [91] 12 Sep, 2013 Lawrence Kolaczkowski The patent describes benzimidazole derivatives role
in facilitating DNA repair, controlling RNA
transcription.
61. WO2013158894 A1 [92] 22 Oct, 2013 Charles Q. Meng The patent describes the Parasiticidal compositions
comprising benzimidazole derivatives, methods
and uses.

ring led to a decreased antiproliferative activity [102]. Gryshchenko
et al. designed and synthesized 5-amino-4-(1H-benzoimidazol-2-
yl)-phenyl-1,2-dihydro-pyrrol-3-ones. These compounds were
assessed for inhibition of FGFR1 kinase activity. Compounds 4a and
4b were found to be most potent with IC50 value of 0.63 mM and
0.32 mM respectively. SAR describes that introduction of hydroxyl
group at meta position of the phenyl ring leads to signicant in-
crease of inhibitory activity towards FGFR1 [103]. Chojnacka et al.
synthesized a series of 4, 5, 6, 7-tetrabromo-1H-benzimidazole
(TBBi) and 4, 5, 6, 7-tetrabromo- 2-methyl-1H-benzimidazole and
evaluated them for the inhibitory activity against protein kinase
rhCK2a catalytic subunit and cytotoxicity against two human can-
cer cell lines. Following evaluation, compound 5 was reported as
the most potent compound of the series [104]. Nayak et al. syn-
thesized benzimidazole-oxindole conjugates derivatives and
determined their cytotoxic activity against human breast cancer
cells (MCF-7). Compounds 6a and 6b showed 43.7% and 43.6% and
64.8% and 62.7% apoptosis, respectively at 1 and 2 mM concentra-
tions [105]. Wang et al. developed novel 5-uorine-benzimidazole-
4-carboxamide analogues. Compound 7 was reported as the most
promising anti-cancer agent with excellent cell inhibitory activity
against HCT116 cells with IC50 of 7.4 mM [106]. A novel series of 3-
(50 -substituted)-benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)
ethoxy)-1H-indazoles derivatives developed by Yan et al. were
evaluated for potent broblast growth factor receptor inhibitory
effect. Compound 8 exhibited excellent in vitro inhibitory activity
against a panel of FGFR-amplied cell lines [107]. Dort et al. syn-
thesized benzimidazole derivatives and evaluated them as bifunc-
tional oncogenic target inhibitors against allosteric Mitogen-
Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-
Kinase (PI3K). Upon evaluation, compound 9 was reported as the
most potent compound with IC50 of 0.015 nM and 191 nM
respectively [108]. A series of (R,E)-N-(7-chloro-1-(1-[4-(dimethy-
lamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-
methylisonicotinamide derivatives was synthesized and assessed
for epidermal growth factor receptor (EGFR) Mutant Non-Small-
Cell Lung Cancer activity by Lelais et al. Compound 10 was re-
ported as the most potent compound of the series [109]. Elancheran
et al. designed and synthesized a series of oxobenzimidazoles de-
rivatives and evaluated them for androgen receptor antagonistic
activity. Compound 11 exhibited the most potent activity against
PC-3 and LNCaP cell lines [110]. Ozkay et al. synthesized thiazole-
benzimidazole derivatives and evaluated them for anti-
proliferative activity. Compound 12 was found to be most active
compound of the series with IC50 of 74.56 mM. Presence of sub-
stituents methoxy, chloro and uoro at para position of phenyl
residue serves to increase the activity of the compound. Methoxy
substituted compound was found to be most potent agents in this
series [111]. Stepanov et al. synthesized and evaluated anti-
proliferative effects in the sea urchin embryo model and in
cultured human cancer cell lines, concluding compound 13 as the
most potent compound of the series with IC50 value of 0.05 mM
[112]. Amongst the various benzimidazole derivatives developed by
Sharma et al., compound 14 exhibited signicant growth inhibitory
activity against several cell lines towards Aurora-A kinase with IC50
value of 0.0l mM [113]. Wang et al. synthesized benzimidazole de-
rivatives and evaluated them for antiproliferative activity. Com-
pound 15 was demonstrated as the most potent tubulin
712 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

polymerization inhibitory agent with IC50 of 1.5 mM. It exhibited
antiproliferative activity against A549, HepG2 and MCF-7 with GI50
of 2.4, 3.8 and 5.1 mM, respectively [114]. Reddy et al. developed a
series of benzimidazole derivatives and evaluated their anti-
proliferative activity against three human tumor cell lines i.e.
lung (A549), breast (MCF-7), and cervical (HeLa). Compounds 16a-
16c were found to be most potent growth inhibitory agents with
IC50 values in the range of 0.83e1.81 mM. Structural variations and
modications on the ring of pyrazolo-benzimidazole derivatives
led to compounds with different cytotoxic activities. SAR studies in
these hybrids demonstrated that compounds with mono-
substituted halogens (uorine, chlorine, and bromine) on the
benzimidazole ring, exhibited more potent effects [115]. Kamal
et al. synthesized a series of arylpyrazole linked benzimidazole
conjugates and evaluated their growth inhibitory activity against
various cell lines. Compounds 17a-17f were found to be most active
of the series [116]. Gao et al. synthesized and biologically evaluated
a series of benzimidazole acridine derivatives as potential DNA-
binding and apoptosis-inducing agents. Following evaluation,
compound 18 was reported to be the most potent [117]. Amongst
the various benzimidazole derivatives developed by Kamal et al.,
compounds 19a and 19b exhibited remarkable cytotoxic activity
against most of the cancer cell lines with Gl50 value in the range of
0.79e28.2 mM. Compounds having methoxy groups were found to
have better antiproliferative activity. The activity was also inu-
enced by the presence of weak ring de-activating groups like
uorine and electron releasing groups like methoxy substitution at
benzimidazole ring [118]. Abdullah et al. developed a series of
benzimidazole derivatives and evaluated their activity as dual Poly
(ADP-ribose) polymerases (PARPs) and Dihydroorotate dehydro-
genase (DHODH) inhibitors. Compounds 20a-20d were reported as
most active compounds of the series [119]. Benzimidazole de-
rivatives, synthesized by Erdmann et al. were screened for anti-
cancer activity. Compound 21 was reported as the most potent

Fig. 2. Anti-cancer activity of benzimidazole derivatives.

 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 713

Fig. 2. (continued).

with an EC50 of 2.1 mM against DNA methyltransferases (DNMT3A)
[120]. Amongst the compounds developed by Roopashree et al.,
compound 22 was reported as the most active compound of the
series against HeLa, HCT116 and A549 cells with IC50 value of
18.3 2.1, 19.1 10.1, 34.7 6.3 mM respectively. Compounds
having bis-benzimidazoles bearing p-methoxy- and p-urosulfonyl
groups exhibited signicant cytotoxicity. Further, bis-benzimid-
azoles bearing tolyl and mesityl sulfonyl groups displayed notable
anticancer activity [121]. Benzimidazole substituted derivatives
developed by Kale et al. were screened for antiproliferative activity
against A549 cell lines. Compounds 23a and 23b were found to be
most potent in the series with IC50 values of 12 1.35 mM and
6 2.8 mM respectively [122]. A series of N-cyclometalated benz-
imidazole ruthenium(II) and iridium(III) complexes derivatives was
synthesized by Yellol et al. Following synthesis, these compounds
were screened for antitumor activity against A2780 cells. Com-
pound 24 was found to be most active with IC50 value of
1.22 0.41 mM. SAR studies showed that compounds with phenyl
substitution show increased potency in both Ruthenium and
Iridium complexes in compared to their parent compounds in all
cell lines. In general, ruthenium complexes were found to be more
active than the corresponding iridium complexes [123]. Kumar
et al. synthesized a series of s-triazine bearing benzimidazole
substituted derivatives and assessed their anti-cancer activity
against MCF-7, MDAMB-231, HT-29 and HGC-27 cell lines.
Following evaluation compounds 24a and 24b were reported as the
most active compounds with IC50 values of 4.8 0.5, 8.3 1.1,
9.8 0.4 1 and 5.1 0.2 mM and 9.5 1.6, 10.3 0.2, 8.3 0.77
714 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 2. (continued).

9.2 0.0 mM respectively [124]. Benzimidazole substituted de-
rivatives developed by Varshney et al. were screened for in vitro
anti-cancer activity against normal human blood cells (PBMCs),
human hepatocellular carcinoma (Hep3B), human breast adeno-
carcinoma (MCF 7) and human cervical carcinoma (HeLa) cell lines.
Compound 25 was found to be most potent of the series with IC50
values of 23 2.3, 40.50 1.6, 24.20 3.2 and 05.34 1.2 47 mM
respectively [125]. Shi et al. synthesized N-(2-phenyl-1H-benzo[d]
imidazol-5-yl) quinolin-4-amine derivatives and assessed their
VEGFR-2 kinase inhibitory activity. Compound 27 exhibited the
most potent inhibitory activity against VEGFR-2 with IC50 of
0.03 mM and it also showed the highest anti-cancer activity against
the tested cancer cell lines with IC50 of 1.2 mM against MCF-7 and
13.3 mM against Hep-G2 [126]. Temirak et al. designed and syn-
thesized 2-furyl benzimidazoles and evaluated their anti-cancer
activity. Compound 28 displayed most promising antiangiogenic
effect against VEGFR2 kinase with IC50 value of 6.98 mg/mL [127].
Kalalbandi et al. synthesized benzimodazole derivatives and
assessed their cytotoxic activity. Compound 29 was found to
display excellent signicant activity against A549 (Human lung
carcinoma) and 8E5 (Human; Acute Lymphoblastic Leukemia) cell
lines with IC50 value of less than 10 mg/ml against both the cell lines
[128]. In a series of benzimidazole derivatives synthesized by Yoon
et al., compound 30 was found to have potent anti-cancer activity
against three different types of cancer cells derived from colon
(HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM)
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 715

Fig. 2. (continued).

with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 mM.
From the results it was observed that both electron withdrawing
groups (-nitro, triuoromethyl) as well as electron donating groups
(-methyl, -hydroxy, -dimethylamino) do not affect the activity
[129]. Guan et al. designed and synthesized bezimidazole carba-
mates bearing indole moiety and evaluated their antiproliferative
and antitubulin activity. Compound 31 displayed most promising
antiproliferative activity against SGC-7901, A-549 and HT-1080
human cancer cell lines with IC50 values of 0.098 0.002,
0.15 0.05 and 0.13 0.07 mM respectively [130]. Benzimidazole
derivatives developed by Nakao et al. were evaluated for activity
against prostate cancer. Amongst the synthesized derivatives,
compound 32 was reported to elicit best activity with IC50 value of
0.67 mM. A benzyl group was used at the 4 position, and the
derivatives bearing benzimidazole ring substituents were evalu-
ated. Some derivatives with substitution at the 5 position exhibited
potent inhibitory activity [131]. Liu et al. developed benzimidazole
analogues and evaluated their in vivo anti-angiogenic and anti-
tumor activities. Compounds 33a, 33b, and 33c displayed most
promising cytotoxic effects on HUVEC and MDA-MB-31 cells, and
antagonized VEGF-A165/NRP-1 binding [132]. Amongst the various
anti-cancer derivatives developed by Xu et al., compound 34 was
found to be the most potent derivative. The more active inhibitory
activity of compound may be due to the presence of Boc group. This
nding suggests that the existence of 5,6-dimethyl-benzimidazole
ring, and substitution of the imidazolyl-3-position with a naph-
thylacyl or 4-bromophenacyl group, were important for modu-
lating inhibitory activity of cell growth [133]. Madabhushi et al.
716 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 2. (continued).

synthesized benzimidazole derivatives and evaluated their anti-
cancer activity. Compound 35 emerged as the most potent anti-
cancer agent against human cancer cell lines A549, MCF-7, DU145
and HeLa with IC50 value of 5.2 0.24, 9.8 0.26, 12.3 0.44,
11.1 0.52 respectively [134]. Wang et al. developed benzimidazole
derivatives and evaluated their tubulin inhibitory activity. Com-
pound 36 displayed most promising antiproliferative activity on
human cancer cells, NCI-H460, Colo205, K562, A431, HepG2, Hela
and MDA-MB-435S with IC50 values of 0.040, 0.050,0.006, 0.026,
1.774, 0.452 and 0.052 mM, respectively [135]. Shao et al. synthe-
sized benzimidazole derivatives and evaluated their anti-cancer
activity. Compounds 37a and 37b were more cytotoxic than 5-
uorouracil against all tested four human cancer cell lines, with
IC50 values ranging from 2.03 to 10.55 mM and 1.06e12.89 mM,
respectively. SAR studies suggest that the introduction of small
electron-donating groups eCH3 or eOCH3 at para-position of
phenyl ring increases anticancer activities while big electron-
donating groups eCH2CH2CH2CH3 or eCH(CH3)2 showed decrease
in the antitumor properties [136]. Amongst the various benzimid-
azole derivatives developed by Paul et al., compound 38 exhibited
remarkable anti-cancer activity towards colon and prostate cancer
cell lines at ve dose concentrations with GI50 values of 0.34
and0.31 mM respectively. SAR study of the compounds shows role of
amines at C2-position of quinazoline for their antitumor activity. In
general, it was observed that the heteroaryl rings and electron rich
aryl groups at C2- position of quinazoline showed better antitumor
activity than the ones with an aliphatic chain [137]. Elshihawy et al.
designed and synthesized benzimidazole derivatives and evaluated
them for methionine synthase inhibitory activity. Compounds 39a
and 39b were found to be the most active compound of the series
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 717

Fig. 2. (continued).

with IC50 values of 20 mM and 18 mM and respectively [138]. Yoon
et al. synthesized a series of antitumor compounds. Antitumor
activity was established against two different cancer cell lines MCF-
7 and MDA-MB-468. Compound 40 was found to be most potent
compound of the series with IC50 value of 49.63 mM and 46.33 mM
respectively. The structure activity relationships analysis reveals
that the compound interact with receptor primarily due to
hydrogen bonding as well as hydrophobic and mild polar in-
teractions. The OeH group of compound is hydrogen bonded
strongly to Glu288 and the dimethylamino group was not able to
form a hydrogen bond. Due to this eOH group may be responsible
for increased activity [139]. Shi et al. developed a series of N-(2-
phenyl-1H-benzo[d]imidazol-5-yl) quinazolin-4-amine de-
rivatives and evaluated them for c-Met and VEGFR-2 activity.
Compound 41 was found be most potent with of IC50 of 0.05 mM and
0.02 mM respectively [140]. Benzimidazole derivatives developed
by Song et al. were tested against Checkpoint kinase1 (Chk1).
Following evaluation, compounds 42a-42c were reported to be the
most potent with IC50 values of 4.05, 6.23, and 2.33 mM respectively
[141]. A series of several derivatives of benzimidazole carboxamide
was synthesized by Zhou et al. Following synthesis, compound 43
was found to be most active of the series. In both benzimidazole
718 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 2. (continued).

and tricycle benzimidazole analogues, the analogues with uo-
roethoxy substituent had three times higher inhibition potencies
than the respective analogues having a uoroethyl triazole group
[142]. Benzimidazole derivatives, synthesized by Kamal et al. were
screened for cytotoxic activity. Compounds 44a-44c were reported
to be most potent against various tested cell lines with GI50 values
in the range of 0.01e2.1 mM. The introduction of substituents such
as ouro, chloro and bromo at 4-position of the benzimidazole ring
improved the activities. However, electron releasing groups like
methoxy and methyl substituentproduced moderate cytotoxic ac-
tivities [143]. Amongst the compounds developed by Zimmermann
et al., compound 45 was reported as the most active compound of
the series against farnesyl binding pocket of PDEd with nanomolar
afnity [144]. Maji et al. synthesized a series of benzimidazole-
carbazole conjugates derivatives and assessed their anti-cancer
activity as telomerase inhibitors. Following evaluation, compound
46 was reported as the most active compound with IC50 value of
0.6 0.01 mM [145]. Diuoro-dioxolo-benzoimidazol-benzamides
substituted derivatives were developed by Richter et al. Com-
pound 47 was highly selective CK1d-specic small molecule in-
hibitor with increased biological activity. Diuoro-
dioxolobenzoimidazole analogues were found to be more potent
than benzimidazole-carbazole [146]. Lu et al. designed and syn-
thesized a series of anti-cancer compounds and evaluates them as
tubulin inhibitors. Compounds 48a and 48b were found to be most
active of the series [147]. Li et al. evaluated in vitro antitumor ac-
tivity of numerous benzimidazole derivatives, concluding com-
pounds 49a and 49b as the most active compounds of the series
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 2. (continued).
against A549, MDA-MB-231, A375 and HCT116 cancer cells using
the MTT assay [148]. Hu et al. synthesized a series of antitumor
compounds. Antitumor activity was established in vitro against
three human cancer cell lines viz human lung carcinoma cell lines:
A549, human leukemia cell line: K562, and human prostate cancer
cell line: PC-3. Compound 50 was found to be most potent in the
series. Preliminary structure-activity relationship of derivatives
revealed that cyclic secondary amines substitutions were benecial
for increasing the cytotoxicity of the compound compared with
open chain secondary amines due to little steric hindrance [149]. A
number of benzimidazoles clubbed with triazolo-thiadiazoles and
triazolothiadiazines were synthesized by Husain et al. These were
evaluated for anti-cancer activity. Compound 51 was reported to
have signicant growth inhibition with GI50 values ranging from
0.20 to 2.58 mM. The anticancer activity was inuenced by the
presence of electron withdrawing group like chloro on ortho, meta
or para position on aromatic ring. Compound having chloro group
on para position of phenyl ring, showed an increased activity.
719
Similarly the same group disubstituted on meta and para positions
showed synergistic action [150]. Amongst the compounds devel-
oped by Mavrova et al., compounds 52a and 52b were found to have
promising antiproliferative effects against HT-29 with IC50 values of
0.85 mM and 2.83 mM respectively [151]. Wang et al. synthesized
benzimidazole based compounds and determined their anti-cancer
activity. Compounds 53a and 53b were found to be the most active
derivatives against human tumor cell lines and more active than
cisplatin [152]. Puttaraju et al. synthesized microwave assisted
derivatives of dihydrobenzo [4,5]imidazo[1,2-a] pyrimidin-4-ones
and evaluate them for anti-cancer activity. Compound 54 found
to be the most potent cytotoxic agent. The coumarin substituted
compound was found to be the most potent cytotoxic agent [153].
Amongst the compounds synthesized by Chen et al., compound
55a-55c exhibited in vitro inhibition of hTERT expression, telome-
rase and suppression of cancer cell growth [154]. Sharma et al.
synthesizd a series of novel regioisomeric hybrids of quinazoline-
benzimidazole compounds. Synthesized compounds were
720 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 2. (continued).

screened for in vitro antitumor activities against various tumor cell
lines. Compound 56 was found to be more active than the known
drug, 5-uorouracil [155]. Zheng et al. synthesized a series of
benzimidazole derivatives and evaluated their anti-cancer poten-
tial. Following in vitro evaluation, it was reported that compound
57could be a promising anti-cancer agent against U937, K562,
A549, LoVo and HT29 cancer cell lines. The introduction of small
group substituent such as methyl, methylthio and methyl sulfonyl,
at 2-position of pyrimidine ring improved the activity [156].
Benzimidazole derivatives synthesized by Paul et al. were screened
for their anti-cancer activity. Compound 58 was found to be most
potent against leukemia, colon cancer and breast cancer cell lines
[157]. Miller et al. synthesized a series of benzimidazole derivatives
and determined their phosphoinositide 3-kinase inhibitory po-
tential. Compound 59 was reported as the most potent compound
of the series with IC50 value of 0.003 mM [158]. Amongst the
benzimidazole synthesized by Wang et al., compound 60 showed
strong activity in several cellular assays and demonstrated in vivo
efcacy in mouse xenograft pancreatic cancer [159]. Guo et al. re-
ported compound 61 to have appreciable inhibitory activity against
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 721

Fig. 2. (continued).

PKM2 cancer cells with Lactate dehydrogenase (LDH) IC50 value of
3.5 mM. Several simple analogues were designed and synthesized to
test the effect of replacing the sub-optimal benzyl group with a
smaller substituent. The analog lacking the phenyl group lost
biochemical activity [160]. Munuganti et al. synthesized a series of
benzimidazole derivatives and evaluated their activity against
prostate anti-cancer. Following evaluation, it was reported that
compound 62 could be a promising prostate anti-cancer agent with
IC50 value of 4.2 mM [161]. Benzimidazole derivatives synthesized
by Mathew et al. were screened for antitumor activity. Compound
722 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 2. (continued).
63 was found to be most active antitumor agent. The electron
withdrawing group like nitro in the meta position of the phenyl
system exhibited signicant antitumor effects. Eelectron-donating
group such as methoxy and dimethyl amine system in the para
position of the phenyl system were found to have favourable effects
on the activity ratio [162]. Amongst the benzimidazole synthesized
by Iqbal et al., compounds 64a and 64b showed more potent
antiproliferative activity against HCT 116 with IC50 value of 0.3 and
1.4, mg/ml respectively [163]. Masoud et al. synthesized a series of
benzimidazole derivatives and evaluated their chemotherapeutic
potential. Following evaluation, it was reported that compounds
65a and 65b could be a promising anti-cancer agents against HCT
116 and HEPG2 cell lines [164]. Benzimidazole derivatives synthe-
sized by Rashid et al. were screened for their anti-cancer potential.
Compound 66 was found to be most signicant growth inhibitory
agent of the series. It could be noted that electron donating groups
on the phenyl ring at 5-position of oxadiazole moiety have great
inuence on anticancer activity Electron withdrawing groups like
eCOOH and eCO did not show remarkable anticancer activity
[165]. Husain et al. developed a series of benzimidazole bearing
oxadiazole and triazolo-thiadiazoles derivatives and assessed their
anti-cancer activity. Compound 67 was found to be most active
with Gl50 values ranging from 0.49 to 48.0 mM. The compound
substituted by bromo group on ortho position increases the activity
[166]. A series of novel [1,2,4]triazino[4,5-a] benzimidazole was
designed and developed by Mattson. The compounds were inves-
tigated for antitumor activity. Consequently, compound 68 was
found to be most potent against human breast adenocarcinoma cell
line (MCF7) with IC50 value of 0.0390 mM [167]. Kamal et al.
developed benzimidazole derivatives and assessed their anti-
cancer potential. Compounds 69a and 69b were found to be most
promising amongst the series. Substitution on the terphenyl moiety
of benzimidazole derivatives, 3,4 dimethoxy and 3,4,5-trimethoxy
containing compounds showed increased anticancer activity
against most of the cancer cell lines [168]. Determann et al. syn-
thesized benzimidazole as anti-cancer agents. Compound 70 was
found to be most active compound of the series [169]. Amongst the
benzimidazole derivatives developed by Wang et al., compound 71
emerged as the most potent anti-cancer agent [170]. Bacharaju et al.
designed a novel series of benzimidazole and tested them for their
antimitotic activity, compound 72 displayed the most promising
antimitotic activity with IC50 value of 1.66 mM. Compound bearing
piperidine moiety showed highest activity whereas compounds
having pyrrolidine were equipotent to morpholine. Overall results
indicate that the cyclic amines have higher activity when compared
to aliphatic amines [171]. Liu et al. synthesized various benzimid-
azole derivatives and evaluated their antitumor activity against
A549, HCT116, HepG2, PC-9 and A375 using MTT assay. Compound
73 was found to be excellent cancer inhibitory agent against the
tested cancer cells with IC50 value ranging from 4 to 17 mM [172].
Several derivatives of benzimidazole moiety synthesized by Alka-
htani et al. were screened for anti-cancer activity. The anti-
proliferative evaluation demonstrated compound 74 as the most
potent of the series. From results it was seen that the methyl or
isopropyl substituted compounds have increased cellular potency
[173]. A series of benzimidazole derivatives was developed by
Pothier et al. These were analyzed for in vitro and in vivo selective
CRTh2 receptor antagonistic chemotype activity. Out of the syn-
thesized compounds, compound 75 was found to be the most
potent molecule having an IC50 value of 388 nM. SAR studies sug-
gest that the potency of the compounds was dependant on both,
the type of connecting group and the length of the n-alkyl chain.
Compound having methyl and phenyl substitution was found to be
less active and the length of n-alkyl chain increased the activity
proportionately [174]. Fagan et al. synthesized a series of imidazo[5,
4-f]benzimidazolequinones and iminoquinone and evaluated their
biological activities. Amongst the synthesized compounds, com-
pound 76 was reported as the most active anti-cancer agent [175].
Omar et al. designed a novel series of benzimidazole analogues and
tested them to determine their cytotoxicity activity against breast
cancer cell line MCF-7. Compound 77 was found to be most active
compound of the series. Structure-activity relationship of de-
rivatives was investigated. The most active compound was fond to
have 4-pyridyl as substituent in position 1 of the pyrrole ring which
may act as hydrogen bonding acceptor [176]. Schneider et al. syn-
thesized benzimidazole derivatives and evaluated them for in vitro
CK2 inhibitory activity against human prostate cancer cells LNCaP.
Upon evaluation, compound 78 was reported as the most potent
compound with half maximal lethal dose (LD50) of 4.75 1.02 mM
[177]. Certal et al. synthesized a new series of benzimidazole and
benzoxazole-pyrimidone derivatives and assessed them for treat-
ment of phosphatase and TENsin homologue (PTEN)-decient
cancers. Compound 79 was reported as the most potent compound
of the series. The SAR study showed that N-methyl benzimidazole
compound resulted in slight improvement of activity, compared to
5-uoro derivatives [178]. Jain et al. synthesized a series of benz-
imidazole derivatives and evaluated their telomerase inhibitory
properties. Compound 80 was found to be most active compound of
the series [179].
2.2. Anti-inammatory and analgesic activity
Inammation is a vital part of the body's immune response. The
traditional signs and symptoms of inammation are heat, redness,
pain, swelling and loss of function. Non-steroidal anti-inamma-
tory drugs (NSAIDs) are used to treat inammation owing to their
inherent capability of inhibiting cyclooxygenases (COXs).
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 723

Cyclooxygenases are involved for the biosynthesis of prostaglandin
from arachhidonic acid [180e182]. Several benzimidazole based
analgesic and anti-inammatory agents have been synthesized by
medicinal chemists Fig. 3.
Amongst the benzimidazole derivatives developed by Boggu
et al., compound 81 displayed highest Nuclear factor B (NF-B)
with IC50 of 1.7 mM. Unsubstituted benzimidazole with one carbon
spacer to the phenyl ring with methoxy group provided more
pharmacophore for the potential inhibition of the activity [183].
Benzimidazole analogues were evaluated for selective PI3Kd
inhibitory activity by Shin et al. Compounds 82a and 82b displayed
potent PI3Kd activity. Replacement of the phenyl moiety with a
pyridine ring resulted in good oral bioavailability [184]. Amongst
the benzimidazole derivatives synthesized by Tatani et al., com-
pound 83 displayed most potent activity against gout with IC50 of
0.062 mM. Replacement of adenine with the benzimidazole moiety
considerably enhanced the inhibitory activity against both hCNT2
and rCNT2 [185]. Benzimidazole bearing analogues were synthe-
sized and evaluated for antinociceptive activity by Kamil et al.
Compounds 84a-84c elicited maximum analgesic activity. The SAR
studies show that derivatives containing nitro group at ortho po-
sition of the phenyl ring displayed better analgesic effects with

Fig. 3. Anti-inammatory and analgesic activity of benzimidazole derivatives.

724 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 3. (continued).

early onset and longer duration of action as compared to the meta-
and para-nitro-substituted derivatives [186]. In a series of benz-
imidazole analogues developed by Bansal et al., compounds 85a
and 85b displayed potent anti-inammatory activity. The eCH3 and
eOCH3 groups have marginally decreased the immunostimulation
which suggest that an electron releasing group may not be
favourable for stimulant actions on immune system. A large bulky
group capable of exhibiting H-bonding as well as lipophilic in-
teractions such as unsubstituted aryl or heteroaryl moiety linked
through H-bond acceptor linker such as eCO, eCS, eCO, eNH, and
others at the 5-position may increase immunostimulatory effects of
the compounds [187]. Amongst the several benzimidazole de-
rivatives developed by Kumar et al., compounds 86a-86d exhibited
highest anti-inammatory activity [188]. Among the various
benzimidazole derivatives developed by Kim et al., compound 87
was found to be most active against Janus kinase (JAK1) [189].
Benzimidazole derivatives synthesized by Khanapur et al. were
evaluated for anti-inammatory activity. Compound 88 exhibited
signicant anti-inammatory activity. On substituting 7 position
with ester followed by acetamide bond linked different heterocyclic
moieties lead to increase in activity. Among different heterocylces,
fused bicyclic was found active over six membered and ve
membered moieties [190]. A series of benzimidazole derivatives
was developed and evaluated for anti-inammatory activity by
Bansal et al. Compounds 89a and 89b were found to be most active
anti-inammatory agents [191]. Kankala et al. developed a series of
benzimidazole and evaluated their in vivo analgesic and anti-
inammatory activity. Compounds 90a and 90b were reported to
be the most potent compound of the series [192]. Nezhawy et al.
synthesized benzimidazole derivatives and evaluated their anti-
inammatory potential. Compounds 91a and 91b were found to
exhibit maximum anti-inammatory activity. Relatively high anti
inammatory activity of compound may be attributed to the
presence of the electron-donating methoxy group at 3- and 4-
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
positions in pyrid-2-yl compounds while bulky substituents such as
methyl and methoxy groups at the 3-, 5- and 4-positions in pyri-
dine reduce the activity [193]. Dixit et al. designed a series of
benzimidazole and tested them for analgesic activity. Among the
synthesized molecules, compound 92a and 92b were found to be
most active against analgesic agents [194]. A series of benzimid-
azole derivatives developed by Banoglu et al. was evaluated for
anti-inammatory action. Consequently, compound 93 was found
to be the molecule with highest anti-inammatory activity [195].
Murray et al. synthesized benzimidazole derivatives and evaluated
their PI3Kd inhibitory potential. Compound 94 was found to exhibit
maximum anti-inammatory activity [196]. Amongst the com-
pounds developed by Kaushik et al., compounds 95a and 95b were
identied as the most potent anti-inammatory agents. From SAR
studies, it seems that both electron donating and withdrawing
group played role in the potent compounds [197].
2.3. Anti-microbial activity
Some microorganisms have become resistant to conventional
antibiotics are often abused/overused against microbial pathogens.
So, currently various classes of antibiotic compounds are being
synthesized and used in the treatment and prevention of microbial
infections [198]. The benzimidazole moiety is a versatile lead
molecule in the pharmaceutical drug development and has a broad
range of biological activities such as antibacterial [199] and anti-
fungal [200,201]. Benzimidazole bearing anti-microbial agents are
shown in Fig. 4.
Zhang et al. synthesized benzimidazole quinolones-based de-
rivatives and determined their antibacterial activity. Compound 96
exhibited minimum inhibitory concentration (MIC) value in the
range of 0.0312e8 mg/mL against Staphylococcus aureus (S. aureus)
and Escherichia coli (E. coli). The substitution of chlorine atom by
nitro group was not benecial for the antibacterial activities. These
results manifested that 2,4-dichlorophenyl derivative should be
worthy to be further investigation as potential antimicrobial agent
[202]. Jeyakkumar et al. synthesized several berberine-
benzimidazole hybrids analogues and evaluated them for anti-
microbial activity. Among the synthesized compounds, compound
Fig. 4. Anti-microbial activity of benzimidazole derivatives.
725
97 was found to be the most potent compound against Methicillin-
resistant Staphylococcus aureus MRSA, E. coli, and Salmonella typhi
(S. typhi) with low MIC values in the range of 2e8 mg/mL. Com-
pounds with heptyl group were found to have broad spectrum and
good antibacterial activites [203]. Kaloglu et al. designed a series of
benzimidazol-2-ylidene carbine complexes and evaluated them for
anti-microbial activity. Compounds 98a-98c demonstrated
maximum inhibition against bacterial strains: Enterococcus faecalis
(E. faecalis), S. aureus, E. coli, Pseudomonas aeruginosa (P. aeruginosa)
and the fungal strains: Candida albicans (C. albicans) and Candida
tropicalis (C. tropicalis) [204]. Chandrika et al. synthesized a novel
series of benzimidazole derivatives and evaluated their antifungal
potential. Consequently, compounds 99a-99c emerged as the best
antifungal agents against azole-resistant fungal strain C. albicans
ATCC 64124 (strain B) [205]. Amongst the various benzimidazole
derivatives developed by Fang et al., compound 100 elicited
maximum anti-microbial activity against Saccharomyces cerevisiae
(S. cerevisae), MRSA and Bacillus proteus (B. proteus) with MIC values
of 1, 2 and 4 mg/mL respectively. The replacement of pentyl frag-
ment in hybrid by ethyl or propyl group lead to weaker activity
against B. proteus [206]. Patil et al. synthesized a series of benz-
imidazole based compounds and evaluated their anti-microbial
activity. Compounds 101a and 101b were reported to be the most
active anti-microbial agent. SAR studies show that the derivatives
bearing the electron withdrawing groups retained the activity. The
replacement of 2-phenyl and 6,8-dichloro groups on the quinazo-
linone part slightly increased activity [207]. In another series of
benzimidazole-based N-heterocyclic carbene derivatives devel-
oped by Haque et al., compounds 102a and 102b was reported to
exhibit excellent antibacterial activity against Gram negative (E.
coli) and Gram positive, Bacillus subtilis (B. subtilis) bacteria [208].
Stolic et al. synthesized a series of benzimidazole derivatives and
evaluated their antibacterial activity. Amongst the synthesized
compounds, compound 103 depicted remarkable antibacterial ac-
tivity against S. aureus, Streptococcus pneumoniae (S. pneumoniae),
Streptococcus pyogenes (S. pyogenes) and Moraxella catarrhalis
(M. catarrhalis) respectively [209]. A series of thiadiazole bearing
benzimidazole based derivatives was synthesized by Ramprasad
et al. and screened for anti-microbial activity. Compounds 104a-
726 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 4. (continued).
104c were found to be most active compounds of the series [210].
Mavrova et al. designed a series of benzimidazole derivatives and
evaluated them for antibacterial activity. Compound 105 demon-
strated maximum inhibition against B. subtilis, S. aureus, Salmonella
abony (S. abony) and E. coli with MIC values of 0.125, 0.016, 0.50 and
0.50 mg/mL, respectively [211]. Mehboob et al. synthesized a novel
series of benzimidazole derivatives and evaluated their antibacte-
rial potential. Consequently, compounds 106a-106c emerged as the
best antibacterial agents against both Francisella tularensis
(F. tularensis) and S. aureus and its methicillin-resistant strain,
MRSA [212]. Amongst the various benzimidazole derivatives
developed by Kumar et al., compounds 107a-107c elicited
maximum antibacterial activity against Gram-positive bacteria
(Micrococcus luteus MTCC 2470, S. aureus MTCC 96, S. aureus MLS-16
MTCC2940, Bacillus subtilis MTCC 121) and Gram-negative bacteria
(E. coli MTCC 739, P. aeruginosa MTCC 2453, Klebsiella planticola
MTCC 530 and C. albicans MTCC 3017). Their activity was found to
be almost equal to the standard drug, Ciprooxacin. SAR studies
show that presence of unsaturation and substituents along with
two nitrogen atoms in the imidazole ring were responsible for
potential activity [213]. Reddy et al. synthesized a series of benz-
imidazole based compounds and evaluated their anti-microbial
activity. Compound 108 was reported to be the most active anti-
fungal agent against Aspergillus niger (A. niger) at 100 mg/well
equivalent to the standard drug, Ketoconazole. Presence of electron
withdrawing substituents on the aromatic ring increases the ac-
tivity. Chloro-substituted pyrazolyl benzimidazole was found to be
potent against A. niger [214]. In another series of benzimidazole
derivatives developed by Seenaiah et al., compound 109 was re-
ported as the most potent anti-microbial agent against S. aureus
(29 mm, MIC 12.5 mg/mL) and Penicillium chrysogenum
(P. chrysogenum) (38 mm, MIC 12.5 mg/mL) [215]. In another series
of benzimidazole derivatives developed by Damu et al., compounds
110a and 110b were reported to exhibit excellent potency against
Candida utilis (C. utilis). They were found to be more potent than the
clinically used drug, Fluconazole [216]. Chen et al. synthesized a
series of pyrimidine-benzimidazol derivatives and evaluated their
anti-microbial activity. Amongst the synthesized compounds, 111a
and 111b depicted remarkable antibacterial activity against Steno-
trophomonas maltophilia (S. maltophilia) [217]. A series of
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 4. (continued).
benzimidazole based derivatives synthesized by Nguyen et al. was
screened for antibacterial activity. Compound 112 was found to be
most active compound of the series [218]. Several benzimidazoles
were developed by Janupally et al. and screened for antibacterial
activity. Amongst the synthesized molecules, compound 113
showed best antibacterial activity [219]. Amongst the benzimid-
azole derivatives developed by Grillot et al., compound 114 was
reported to be highly active, when evaluated against broad-
spectrum Gram-positive bacteria [220]. A number of 7-(benzimi-
dazol-1-yl)-2,4-diaminoquinazolines derivatives was synthesized
and assessed for antibacterial potential by Lam et al. Upon evalu-
ation, compound 115 was reported as the most active compound of
the series against S. aureus with MIC of 0.015 mg/mL. Compound
containing a thiazol-2-yl group in the 2-position of the benzimid-
azole was reported to be highly potent and selective [221]. Babu
et al. synthesized a series of 2-(3-methylindolyl)benzimidazole
derivatives and evaluated them for anti-microbial action. Conse-
quently, compound 116a and 116b demonstrated highest anti-
microbial activity against S. aureus MLS-16 and B. subtilis bacteria
[222]. Amongst the compounds synthesized by Desai and Kotadiya,
compounds 117a- 117e showed remarkable antibacterial and
727
antifungal activity against the different microbial strains [223]. A
series of benzimidazole bearing cyanopyridine and 4-
thiazolidinone motifs based derivatives synthesized by Desai
et al. was screened for anti-microbial activity. Compounds 118a-
118d were found to be active anti-microbial agents. SAR studies
suggest that it was that the presence of electron donating groups
remarkably enhanced the antimicrobial activity of newly synthe-
sized compounds [224]. Several pyridyl benzimidazoles were
developed by Desai et al. and screened for anti-microbial activity.
Amongst the synthesized molecules, compound 119a and 119b
were found to be most potent anti-microbial agent against Gram-
positive (S. aureus and Streptococcus pyogenes), Gram-negative
(E. coli and P. aeruginosa) bacteria and fungi (C. albicans, A. niger and
A. clavatus) strains [225]. Amongst the benzimidazole derivatives
developed by Patel et al., compounds 120a and 120b were active
against C. albicans whereas compounds 120c and 120d were active
against S. aureus. The activity of compounds with different alkyl/
aryl substituents indicate the importance of functional groups in
enhancing the antimicrobial activity of a compound [226]. Amongst
the compounds synthesized by Joshi and Parikh, compounds 121a-
121c showed remarkable antibacterial and antifungal activity
728 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 4. (continued).

against P. aeruginosa and C. albicans strains. From the SAR study
data, it was observed that the derivatives with electron-
withdrawing functional groups were more bioactive than those
with electron-donating functional groups [227]. A number of
benzimidazole bearing pyrazoline derivatives were synthesized
and assessed for anti-microbial potential by Desai et al. Upon
evaluation, compounds 122a-122c were reported as the most
potent compounds of the series. SAR of the series showed that
antibacterial activity was considerably affected by substitution
pattern on the phenyl ring and the incorporation of electron-
withdrawing groups was responsible for enhancing the activity
against most of the test microorganisms [228]. Ravindernath et al.
synthesized a series of benzo[d]imidazolyl chromeno [2,3-d]pyr-
imidinones analogues and evaluated them for antibacterial action.
Consequently, compounds 123a and 123b displayed excellent ac-
tivity and were found to be more active than the standard drug,
Ciprooxacin [229]. Among the compounds synthesized by Nimesh
et al., compound 124 was found to be the most remarkable anti-
bacterial agent against E. coli strain [230]. Zhang et al. synthesized
benzimidazole derivatives and tested them for anti-microbial
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 729

Fig. 4. (continued).

activity. Compound 125 was found to be one of the most potent
compounds [231]. Amongst the compounds synthesized by Ranjith
et al., compound 126 displayed good anti-microbial activity against
S. aureus, (Gram-positive), E. coli and Klebsiella pneumoniae (K.
pneumoniae) (Gram-negative), antifungal activity against
C. albicans, Aspergillus avus (A. avus) [232]. In another series of 2-
arylbenzimidazole derivatives developed by Zhou et al.,
compounds 127a-127e were reported to exhibit maximum potency
against Bacillus cereus (B. cereus) with MIC values of 25 mM [233]. A
series of benzimidazole-based analogues was synthesized by
Kumar et al. and evaluated for antibacterial activity. Following
evaluation, compound 128 found to elicit good activity [234]. In
another series of benzimidazole derivatives developed by Savaliya
et al., compound 129 was reported to exhibit excellent potency
730 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 4. (continued).

against Gram positive bacteria S. aureus. SAR of the series indicated
that 4-nitro benzothiazole containing sydnone showed good ac-
tivity against all bacterial and fungal strains [235]. A series of
benzimidazole along with benzthiazole analogues was synthesized
by Sharma et al. and evaluated for anti-microbial activity. As a
result, compound 130 showed good activity against P. aeruginosa
with MIC value of 0.01 mM. SAR studies indicated that methyl-
enedioxy cinnamaldehyde exhibited an increased broad spectrum
activity against the tested microorganisms and hence, was used as a
lead structure to synthesize novel Schiff bases/heterocyclic com-
pounds under microwave irradiation [236]. Parikh and Joshi syn-
thesized various benzimidazole-clubbed chalcone derivatives and
evaluated them for antibacterial and antifungal activity. Amongst
the compounds synthesized, compound 131a was reported as the
most active molecule against Gram-positive bacteria S. aureus with
MIC value of 15.62 mg/mL. Compound 131b was found to be most
active antifungal agent against C. albicans [237]. In a series of pyrido
[1,2-a]benzimidazole derivatives synthesized by Sangani et al.,
compounds 132a-132c were found to be more potent than Ampi-
cillin with MIC of 100 mg/mL. SAR study revealed that antimicrobial
and antitubercular potency of the title compounds depends not
only on the bicyclic heteroaromatic pharmacophore appended
through ether linked aryl ring but also on the nature of the pe-
ripheral substituents and also upon their spatial relationship and
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 731

Fig. 4. (continued).

positional changes [238]. Murthy et al. synthesized various 2-diazo-
benzimidazole based compounds and evaluated their anti-
microbial potential. Compounds 133a and 133b were found to be
the most active compounds of the series [239]. Jain et al. designed a
series of 2-aryl benzimidazole derivatives and evaluated them for
antibacterial activity. Compound 134 was found to be most active
agent against S. aureus, S. feacalis, S. typhi and P. aeruginosa with MIC
of 12.5, 12.5, 6.25 and 12.5 mg/mL [240]. Sathaiah et al. synthesized a
novel series of 6-substituted benzimidazoles and evaluated their
anti-microbial potential. Consequently, compounds 135a and 135b
emerged to be the best antibacterial and antifungal agents [241].
Amongst the various benzimidazole derivatives developed by
Zhang et al., compound 136 elicited maximum antibacterial activity
against MRSA, E. Coli, and P. aeruginosa with MIC values of 2, 4, and
4 mg/mL respectively [242]. Garudachari et al. synthesized a series
of quinoline bearing benzimidazole compounds and evaluated
their anti-microbial activity. Compounds 137a-137d were reported
to be the most active antibacterial agents. Compound 137e was
found to be most active antifungal agent. SAR indicated that chlo-
rine atom on benzimidazole ring and 4-uorophenyl group on
second position of quinoline is responsible for the enhanced anti-
fungal activity [243]. In another series of benzimidazolyl-1,3,4-
732 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 4. (continued).
oxadiazol-2-ylthio-N-phenyl derivatives developed by Patel et al.,
compounds 138a and 138b were reported to exhibit excellent po-
tency against S. aureus. Among compounds active against Shigella
exneri, benzothiazolyl derivatives with chloro, uoro and methoxy
substituents were found potentially active [244]. Krim et al. syn-
thesized a series of 5 benzimidazolyl-2-deoxyuridines and evalu-
ated their antibacterial activity. Amongst the synthesized
compounds, compound 139 depicted remarkable antibacterial ac-
tivity against Gram-positive bacteria S. aureus, MRSA, E. faecalis,
Enterococcus faecalis (E. faecium) and S. pneumonia [245]. Amongst
the various benzimidazole derivatives developed by Bastien et al.,
compound 140a was found to be potent inhibitors of hDHFR [246].
Soni et al. synthesized a series of benzimidazole based compounds
and evaluated their anti-microbial activity. Compounds 141a and
141b showed higher activity against S. aureus and 141c and 141d
were found to have higher activity against E. coli. Compounds 141e
and 141f showed higher activity against C. albicans [247]. In another
series of benzimidazole-pyrazole bearing pyridine nucleus
derivatives developed by Desai et al., compounds 142a-144d were
found to be most potent with MIC value of 25 mg/mL against bac-
terial strains and compounds144e and 144f were found to be most
active with MIC value of 100 mg/mL against fungal strains. SAR
studies show that compounds containing electron-donating groups
showed lower MIC values than the reference drug against different
microbial strains. It has been reported that electron-donating
groups increases the electron density which makes the com-
pounds effective against microorganisms and enhances the anti-
microbial activity [248]. Desai et al. also synthesized a series of
benzimidazole nucleus containing 4-oxo-thiazolidine derivatives
and evaluated their anti-microbial activity. Amongst the synthe-
sized compounds, compound 143a depicted remarkable antibac-
terial activity against E. coli whereas 143b exhibited excellent
antifungal activity against C. albicans strain. The electronic nature of
the substituent groups at 2-position in benzimidazole nucleus led
to a signicant variation in antimicrobial activity. A series of com-
pounds when substituted by electron withdrawing group like NO2
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 733

Fig. 4. (continued).

enhances the antimicrobial activity when present on aromatic ring
[249]. A benzimidazole based series was synthesized by Desai et al.
and screened for anti-microbial activity. Compounds 144a-144d
were found to be most active compound of the series [250].
2.4. Neuro-protective agents
Stroke has been the second leading cause of death and a main
cause of neurological disability in the world over the past decade
[251] Alzheimer's disease (AD), the most common form of de-
mentia, is a chronic neurodegenerative disorder, which is clinically
characterized by impairment in memory, complex cognition,
language, emotion and behavior [252]. In 2015, approximately 46.8
million people worldwide were believed to suffer from AD and this
number was expected to be triple by 2050 with the aging of the
population [253]. Several factors, such as levels of acetylcholine
(ACh) and amyloid-b-peptide (Ab) deposits, play a signicant role
in the occurrence of AD [254]. A number of neuro-protective agents
bearing benzimidazole moiety are represented in Fig. 5.
Various benzimidazole based analogues developed by Mochi-
zuki et al. were tested as in vivo CRF1 receptor antagonists. Com-
pound 145 was found to be most active compound of the series.
SAR studies show that replacement of a chloro group at the 4-
position with a more electron withdrawing cyano group
734 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 4. (continued).

maintained CRF1 receptor-binding activity. The methyl and
methoxy analogues demonstrated activity comparable to that of
the cyano analog. However, the phenyl analog was much less
potent [255]. Coban et al. synthesized various 1H-benzimidazole
derivatives and evaluated them for selective butyrylcholinesterase
inhibitory activity. Amongst the synthesized molecules, compound
146 was found to be the most active [256]. Siddiqui et al. developed
several benzimidazole and phenylhydrazinecarbothiomide hybrids
and determined their anticonvulsant activity. Among the synthe-
sized compounds, compound 147 appeared to be the most active
agent [257]. A series of benzimidazole base derivative was
synthesized by He et al. and assessed for neuro-protective activity.
Consequently, compound 148 demonstrated maximum neuro-
protective potential against metabotropic glutamate receptor 5
(mGluR5) with IC50 value of 6.4 mM [258]. Vangavaragu et al. syn-
thesized a series of benzimidazole based compounds and reported
them as Presequence protease (hPreP) agonists for the treatment of
AD. Compounds 149a and 149b potentially enhanced hPreP-
mediated proteolysis of Ab, pF1b and uorogenic-substrate V as it
helps in the treatment of Alzheimer's disease [259]. Aslam et al.
developed a series of pyrazolobenzothiazines with benzimidazoles
derivatives and investigated them as potential inhibitors of
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 735

inhibitors with IC50 values of 11 and 13 nM respectively [260].

Fig. 4. (continued).
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
Compounds 150a and 150b were found to be most potent AChE
Design and synthesis of styryl benzimidazole derivatives was car-
ried out by Matsumura et al. The synthesized compounds were
evaluated for their imaging of neurobrillary tangles for AD.
Compound 151 expressed good anti-alzheimer's activity [261].
Several 1-heteroaryl-2-aryl-1H-benzimidazole were synthesized
by Kim et al., and were evaluated through measurement of Poly-
cystic Kidney Disease (PKd) using surface plasmon resonance (SPR),
Jun amino-terminal kinases (JNK3 kinase) assay and cell-viability of
human neuroblastoma cells. The results revealed that compound
152 was the most potent cell protective agent with IC50 value of
1.09 mM against toxicity induced by anisomycin, showing a possi-
bility of protective therapeutics in neuronal cell apoptosis [262]. A
series of novel substituted 2-aminobenzimidazoles was designed
and developed by Zhu et al. The compounds 153a and 153b were

Fig. 5. Neuro-protective activity of benzimidazole derivatives.

736 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 5. (continued).
investigated against selective inhibitors for AChE and BuChE and
were reported as potentially useful agents for the treatment of
neurodegenerative diseases [263]. Hu et al. synthesized a series of
benzimidazole derivatives and evaluated them as selective in-
hibitors of Phosphodiesterase-10A. Following evaluation, it was
found that compound 154 could be a promising
Phosphodiesterase-10A inhibitor [264]. Benzimidazole derivatives
synthesized by Tamura et al. were evaluated for their potent neu-
ropeptide Y (NPY) receptor antagonistic activity. Compound 155
was found to be most potent of the series [265]. Tamura et al.
synthesized benzimidazole derivatives as NPY Y5 receptor antag-
onist. Compound 156 was found to have high Y5 receptor binding
afnity with a good absorption, distribution, metabolism and
elimination (ADME) prole leading to in vivo efcacy [266].
Amongst the benzimidazole derivatives developed by Davies et al.,
compound 157 emerged as the most potent NR2B-selective N-
methyl-D-aspartate (NMDA) receptor antagonist with pIC50 value of
more than 7. The SAR addressing the potential lack of CNS pene-
tration predicted by in-silico models, prompted the synthesis of the
des-phenol and uoro analogues since replacing the phenolic OH
would lower the polar surface area and reduce the number of
hydrogen bond donors, and therefore likely have a benecial effect
on the degree of CNS penetration [267]. Ravula et al. synthesized
various benzimidazoles derivatives and evaluated them against
CNS penetrating H1-antihistamines. Amongst them, compounds
158a and 158b were found to be most active compounds of the
series [268]. A series of benzimidazole derivatives designed and
synthesized by Bischoff et al. was assessed for potent g-secretase
modulatory activity. Compound 159 showed the best in vivo
lowering of Ab42. SAR indicated that the replacement of the
methoxyphenyl ring with a methoxypyridyl ring led to improved
drug-like prole and enhanced in vivo activity [269].
2.5. Anti-hypertensive agents
Causes of acute intracerebral hemorrhage (ICH) is found in more
than 50% of patients due to high blood pressure (BP) and is sub-
stantially higher than premorbid levels [270e272]. Lowering BP
long term after stroke is the key for secondary prevention [273]. A
number of anti-hypertensive agents bearing benzimidazole moiety
are reported in Fig. 6.
Ren et al. designed and developed a series of benzimidazoles
based compounds. Amongst the synthesized compounds, 160 was
reported to have anti-coagulant action against arteriovenous
thrombosis with inhibition rate of 85.35 0.72%. Aryl-substituted
pyridine or methyl substitution could increase hydrophobicity,
which may also favor activity [274]. A series of N-phenyl indole
bearing benzimidazole derivatives was synthesized by Zhu et al.
and evaluated for their anti-hypertensive activity. Compound 161
was found to be the most active compound [275]. Several benz-
imidazole containing agents were synthesized by Wang et al.
Compound 162 was found to elicit most effective inhibitory activ-
ities against thrombin with IC50 value of 1.81 nM. Among those
newly synthesized analogues, the introduction of the substituent
group at the ortho or para position could increase anticoagulant
activity, and the ortho position was better than other positions.
However, the anticoagulant activity severely declined once the
substituent group was at the meta position [276]. Li et al. found a
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 737

new class of uorinated based benzimidazole molecules and
investigated their thrombin inhibitory effect. Resultantly, com-
pound 163 was found to be the most active agent against thrombin-
induced platelet aggregation and demonstrated potent activity for
inhibiting arteriovenous thrombosis with an inhibition rate of
73 6%. In this series, the introduction of a methyl substituent on
the benzimidazole ring increased the anticoagulant activity
compared with other derivatives of the series [277]. Okolotowicz
et al. designed a series of 1,5-disubstituted benzimidazoles de-
rivatives and evaluated them for cardiomyogenesis potential.
Compound 164 was found to be most potent compound of the
series. Substitution of electron withdrawing groups led to com-
pounds with diminished potency for cardiomyogenesis. Substitu-
tion with alkoxyphenyl groups, increased cardiomyogenesis.
Hydroxyphenyl-substituted benzimidazole increased cardiomyo-
genesis. However, electron withdrawing substituted
benzimidazoles were generally less potent [278]. A new benz-
imidazole based series of compounds were designed by Han et al.,
in which compound 165 showed remarkable anti-hypertensive
activity with IC50 value of 1.1 nM [279]. Zhu et al. found a new
class of 5-nitro benzimidazole and investigated their anti-
hypertensive activities. Resultantly, compound 166 was found to
be the most active agent against angiotensin II type 1 receptor with
IC50 value of 1.03 0.26 nM. The length of alkyl chain on 2-position
of benzimidazole is very important, and the compound with butyl
chain has the highest activity. The persuasive explanation is that
alkyl chain with suitable length could interact more quickly and
bind more tightly with lipophilic pocket [280]. A new indazole
bearing benzimidazole based series of compounds was designed by
Lamotte et al., in which compound 167 was identied as a potent
AT1 receptor antagonist with IC50 value of 0.006 mM [281]. Zhang
et al. synthesized a novel series of benzimidazole derivatives and

Fig. 6. Anti-hypertensive activity of benzimidazole derivatives.

738 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

Fig. 6. (continued).

described their anti-hypertensive activity. Compounds 168a and
168b were found to be most active amongst all the synthesized
compounds with IC50 value of 3 and 0.1 nM respectively [282].
Nofal et al. synthesized various 1H-benzimidazol-2-yl based ana-
logues and evaluated them for vasorelaxant activity. Amongst the
synthesized compounds, compound 169a- 169d exhibited
remarkable activity when compared with prazosin hydrochloride
[283]. Amongst the compounds developed by Jain et al., compound
170 was found to be selective anti-hypertensive agent [284]. Wang
et al. reported benzimidazole compound 171 as the most active
angiotensin II AT1 receptor antagonist with low toxicity [285].
Zhang et al. reported compound 172 to have appreciable angio-
tensin II AT1 receptor antagonistic activity with low toxicity [286].
Benzimidazole derivatives synthesized by Bai et al. were screened
for their antagonistic effect. Compound 173 was found to be most
active molecule of the series with IC50 values of 8.5 nM respectively
[287].
 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753 739

2.6. Antiviral activity Benzimidazole compounds synthesized by Pan et al. were

Viral infections are one of the vital health problems. Hepatitis A
virus (HAV) infections remain a major cause of acute kidney injury,
acute hepatitis and hemophagocytic syndrome. The treatment of
viral infectious diseases still remains an important challenge
because of the emergence of drug-resistant strains due to the rapid
mutability of the virus [288]. Previous antiviral research has pri-
marily focused on the development of nucleoside analogues but
recently, nonnucleoside derivatives [289] have also received
considerable attention. A number of antiviral agents bearing
benzimidazole moiety are shown in Fig. 7.
evaluated for antiviral activity. Compounds 174a and 174b were
reported as the most potent anti-HIV-1 agents with IC50 values of
3.49 and 58.03 nM respectively. SAR studies indicate that benzene
ring and its N,N-dialkyl amine substitution group were required for
the anti-HIV-1 replication activity. The N,N-dialkyl group, m-
methoxy and p-hydroxyl groups were the most favored sub-
stitutions. The modications on benzimidazole substructure and
the linker also afforded compounds with higher activity than the
hit compound which indicated the possibility to increase activity by
modications on this substructure [290]. In a series of compounds
developed by Ding et al., compounds 175a and 175b were found to

Fig. 7. Antiviral activity of benzimidazole derivatives.

740 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

be active against hepatitis C virus [291]. Monforte et al. reported
compound 176 as a potent inhibitor of HIV-1 non-nucleoside
reverse transcriptase with IC50 value of 0.12 mM [292]. Tonelli et al.
developed a series of benzimidazole and evaluated them for anti-
viral activity. Amongst the synthesized molecules, compounds 177
and 178 displayed most remarkable antiviral activity [293]. Several
benzimidazole analogues designed by Link et al. were tested for
antiviral activity. Consequently, compound 179 showed best anti-
viral activity against hepatitis C virus with half maximal effective
concentration (EC50) value of 31 nM [294]. Tsay et al. reported a
series of benzimdazole based compounds and tested them against
hepatitis C virus. Amongst the synthesized compounds, com-
pounds 180a and 180b displayed signicant antiviral activity with
an EC50 value of 3.0 and 5.5 nM respectively. The attachment of a
methyl group to the benzimidazole nucleus generated hybrids with
remarkable anti-HCV activity. The incorporation of a fused benzene
ring to the coumarin nucleus in the hinged hybrids increased the
activity [295]. Tremblay et al. designed and developed several
benzimidazole based derivatives and tested them for their antiviral
activity. Compound 181 was reported to be a promising antiviral
agent with EC50 value of 0.64 mM [296]. A series of 5-acetyl-2-
arylbenzimidazoles analogues synthesized by Vitale et al. was

Fig. 8. Anti-tubercular activity of benzimidazole derivatives.

 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 8. (continued).
tested for anti-viral activity. Compound 182 was found to be most
active compound of the series with EC50 value of 1.11 mM. SAR
studies indicate that the acetyl group as such, or its corresponding
hydroxyethyl derivatives, are unable to promote antiviral activity in
the series of N-1-unsubstituted benzimidazoles. Phenyl bearing a
2,4-dimethoxy group showed improvement in anti-Bovine Viral
Diarrhea virus (anti-BVDV) activity. Bioisosteric replacement of the
phenyl with a furanyl or pyridinyl ring was partially successful and
fairly good in the case of other compound of the series [297].
2.7. Anti-tubercular activity
Tuberculosis (TB) is a bacterial infection disease caused by
Mycobacterium tuberculosis (M. tuberculosis) and is the second
leading cause of deaths worldwide [298]. Currently, new form of
treatment for tuberculosis such as DOTS (Directly Observed Ther-
apy Short-course) requires a combination of three to four drugs,
which includes isoniazid, pyrazinamide, rifampin and ethambutol
for over a period of 6e12 months [299,300]. A number of anti-
tubercular agents bearing benzimidazole moiety are represented
in Fig. 8.
741
Gobis et al. developed a series of 1H-benzo[d]imidazole based
compounds and determined their in vitro anti-mycobacterial ac-
tivity. Compound 183a- 183d was emerged as the best molecules of
the series against Mycobacterium tuberculosis (M. tuberculosis) and
Mycobacterium bovis (M. bovis) strains with MIC values ranging
from 0.75 to 1.5 mg/mL. Generally, compounds possessing the
cyclohexylethyl substituent at the C-2 position were more active
than those with the longer chain linker [301]. Amongst the benz-
imidazole derivatives developed by Yoon et al., compound 184 was
found to be most active anti-mycobacterial agent with IC50 value of
11.52 mM. It was found that electron withdrawing group sub-
stituents at 4-position in the phenyl ring is important for the ac-
tivity of compounds [302]. Amongst the compounds synthesized by
Gobis et al., compounds 185a-185c displayed highest anti-
tubercular activity against M. tuberculosis strains with MIC values
ranging from 0.8 to 6.2 mg/mL. Substitution with sulfonyl group led
to the loss of activity where in the bulky phenylsulfonyl group
caused a higher loss of activity than the smaller methylsulfonyl one.
The presence of two methyl groups at the C-5 and C-6 positions of
the benzimidazole core confers the highest activity [303]. Chan-
drasekera et al. developed a series of phenoxy alkylbenzimidazoles
742 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

derivatives. These compounds were screened for anti-tubercular
activity against M. tuberculosis. Amongst the developed com-
pounds, compound 186 was found to be most potent with MIC of
52 nM [304]. Several benzimidazole derivatives developed by Barot
et al. were evaluated for in vitro antitubercular activity. Following
evaluation, compounds 187a and 187b were found to be most
potent with MIC of 3.13 and 4.7 mg/mL respectively [305]. Gong
et al. developed benzimidazole substituted derivatives and
screened them for activity against M. tuberculosis. Compounds 188a
and 188b were reported as the most active compound of the series
[306]. Amongst the benzimidazole bearing substituted 2-pyridone
derivatives developed by Desai et al., compounds 189a-189e were
found to be most potent in vitro antitubercular agents with MIC in
the range of 2.76e20.4 mM. Compound bearing Cl group was found
to be most potent antibacterial agents due to its high lipophilicity.
The MIC values of the novel compound conrmed that the presence
of chlorine substituent at meta position gave rise to better phar-
macological potency rather than the same substituent present at
ortho or para positions [307]. A series of 2, 5, 6-trisubstituted
benzimidazole derivatives designed and developed by Park et al.
and was evaluated for anti-tubercular activity. Among the synthe-
sized molecules, compound 190 was found to be the most active
agent having minimum inhibitory concentration (MIC50) value of
0.63 mM [308]. Amongst the 3-cyclohexylpropanoic acid derived
nitrogen heterocyclic analogues developed by Gobis et al., com-
pounds 191a-191d displayed signicant tuberculostatic activity
against M. tuberculosis strains with MIC values ranging from 1.5 to
12.5 mg/mL [309].

Fig. 9. Anti-protozoal activity of benzimidzole derivatives.

 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 9. (continued).
2.8. Anti-protozoal activity
A parasitic infection is a serious global public health problem.
Some infections are enteric, which give rise to diarrhea, and are
considered to be amongst the ve most common causes of death
worldwide. Annually about 1.6 million people of the world's pop-
ulation suffer from one or several neglected tropical diseases
[310e312]. A number of anti-protozoal agents bearing benzimid-
azole moiety are reported in Fig. 9.
A series of 2-anilinobenzimidazoles molecules was synthesized
by Karaaslan et al. The developed series was evaluated for anti-
protozoal activity. Compound 192 was found to be most potent
against Plasmodium falciparum (P. falciparum) with IC50 value of
0.138 0.017 mM [313]. Amongst the 2-arylbenzimidazoles
designed by Keurulainen et al., compound 193 was active against
Leishmania donovani (L. donovani) infected THP-1 cells showing 46%
parasite inhibition at 5 mM. The 4-methylbenzimidazole and 5-
methylbenzimidazole derivative showed interesting SAR.
Although they inhibited axenic amastigotes very similarly at all
concentrations and had similar IC50's, the activities on infected
THP-1 cells differed signicantly. The 5-methyl derivative had
almost no activity, whereas the 4-methyl derivative showed good
activity [314]. Compound 194 was reported as the most potent anti-
leishmanial agent amongst the compounds synthesized by Taha
et al. The IC50 value was found to be 37.80 2.5 mM [315]. Garg et al.
synthesized various 2-substituted benzimidazole derivatives and
evaluated them for anti-helmintics potential. Compounds 195a and
195b were reported as most potent among the synthesized com-
pounds. The SAR designed from the in silico as well as experimental
study revealed that the electron releasing groups increases the
anthelmintic activity. On the contrary, an electron withdrawing
group at both ortho as well as para position of the phenyl ring incurs
less activity [316]. Amongst the various benzimidazole derivatives
developed by Villanueva et al., compound 196 elicited maximum
anti-protozoal activities against Trichomonas vaginalis (T. vaginalis),
Giardia intestinalis (G. intestinalis) and Entamoeba histolytica
(E. histolytica) with IC50 values of 0.0761 0.0094, 0.0083 0.0023
and 0.0298 0.0047 mM respectively [317]. Arteche et al. developed
several derivatives of benzimidazole and screened them for anti-
protozoal activity. Compound 197 elicited excellent antiprotozoal
activity against G. intestinalis, E. histolytica and T. vaginalis with IC50
743
values of 0.021 0.005, 0.006 0.002 and 0.041 0.005 mM
respectively. Compounds with a methyl group or a triuoromethyl
group at position-2 of the benzimidazole nucleus enhance the ac-
tivity [318]. Amongst the derivatives designed by Patle et al.,
compounds 198a and 198b exhibited signicant activity against
leishmanial strains [319]. Amongst the benzimidazole derivatives
synthesized by Keurulainen et al., compound 199 was found to
elicit maximum activity against P. falciparum [320]. Several de-
rivatives of 2,3-dihydroimidazo[1,2-a]benzimidazole designed and
synthesized by Oh et al. were proled for in vitro anti-malarial
activity against L. donovani and Trypanosoma cruzi (T. cruzi). Com-
pounds 200a and 200b exhibited promising anti-leishmanial ac-
tivity against intracellular L. donovani with EC50 values of 3.05 and
5.29 mM respectively. The presence of hydrophobic and sterically
hindered substituent in para position such as tert-butyl, cyclohexyl
or phenyl was also necessary to retain anti-parasitic activities,
while the compounds with hydrogen, ethyl and isopropyl as well as
other compounds containing electron withdrawing group at para
position showed signicant loss of activity [321]. A new series of N-
aryl-2-aminobenzimidazoles was developed and screened by
Ramachandran et al. for their anti-malarial activity against
P. falciparum. Compound 201 was found to be most active of the
series with IC50 value of 36 nM [322]. Shaukat et al. designed and
developed a series of benzimidazole based derivatives. Compounds
202a and 202b were found to have an excellent in vitro leishma-
nicidal activity with an IC50 value of 0.62 mg/mL. Among chloro-
substituted benzimidazoles, the p-isomers were found to be more
effective than the o-isomers [323]. A series of benzimidazole
developed by Saify et al. was tested for in vitro anti-plasmodial
activity against P. falciparum plasmepsin II and human cathepsin
D. Compound 203 displayed signicant anti-plasmodial activity
with IC50 value of 160 nM. SAR analysis indicated that the higher
antiplasmodial activity of compound was due to the extra phenyl
group present at the para position of acetophenone ring [324].
2.9. Miscellaneous
In addition to the above mentioned activities, several other ac-
tivities have been reported by various scientists Fig. 10.
Lutnant et al. developed a series of benzimidazole derivatives
and evaluated them for GluN2B selective NMDA receptor
744 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753

antagonistic activities. Amongst the synthesized compounds,
compound 204 was found to be most active [325]. Kumar et al. also
synthesized pyrazolylbenzo[d]imidazoles derivatives and evalu-
ated them for inhibition of carbonic anhydrase. Compound 205a
and 205b were found to be most potent compounds of the series
[326]. Igawa et al. synthesized a series of 1-(1H-benzimidazol-6-yl)
pyridin-2(1H)-one compounds and assessed their action on
melanin-concentrating hormone (MCH) as an attractive target for
anti-obesity agents. Compound 206 was found to be most active
against Melanin-concentrating hormone receptor (MCHR1) [327].
Siddiqui et al. developed several derivatives of benzimidazoles and
screened them for in vitro a-chymotrypsin inhibitory activity.
Compound 207 was found to be potent with IC50 value of
14.8 0.1 mM [328]. Benzimidazole derivatives developed by Khan
et al. were evaluated for as glycogen synthase kinase-3b inhibitory
activity. Following evaluation, compounds 208a-208d were re-
ported as the most potent compounds. Electron donating groups
were found to confer better activity as compared to the electron
withdrawing groups [329]. Arshad et al. designed and synthesized a
series of 5-bromo-2-aryl benzimidazoles and assessed them for a-
glucosidase inhibition. Compound 209 was reported as the most
potent compound of the series [330]. Yang et al. developed several
benzimidazoles derivatives and screened their phosphodiesterase
10A inhibitory potential. Following evaluation, compound 210 was

Fig. 10. Miscellaneous activity of benzimidazole derivatives.

 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
Fig. 10. (continued).
found to be most potent with IC50 value of 3.73 0.60 nM [331]. A
new series of benzimidazoles was synthesized and tested by
Zawawi et al. for cytokine-induced apoptotic activity in pancreatic
b-Cells activity. Compound 211 was found to be most active of the
series. Hydroxyl (-OH) and methoxy (-OCH3) groups and their
respective positions on the phenyl ring were the preferred substi-
tution required for the activity. The benzimidazole derivatives with
hydroxyl group on the phenyl ring were found to have an activity
pattern, such that more the hydroxyl group, greater is the activity
[332]. Nanda et al. developed benzimidazole derivatives and tested
for Cannabinoid 2 (CB2) receptor agonism. The most potent com-
pound 212 was found to have 92-fold selectivity over CB1. Intro-
duction of an electron withdrawing triuoroethyl group makes
these compounds much less active as CB2 agonists [333]. Bandyo-
padhyay et al. synthesized benzimidazole based analogues and
evaluated them for larvicidal potential. Amongst the synthesized
compounds, compound 213 was found to be the most potent [334].
Nimczick et al. developed a series of new benzimidazole derivatives
and evaluated them for bivalent cannabinoid receptor agonism.
Compound 214 was found to have very promising effect on human
745
cannabinoid receptor type 2 (hCB2R) [335]. Chino et al. synthesized
several benzimidazole derivatives and evaluated them for activity
against phosphodiesterase 10A (PDE10A). Following evaluation,
compound 215 was found to be most potent. Results of a focused
SAR study showed that the introduction of a phenyl ring to the N-1
position on benzimidazole greatly improved inhibitory activity
[336]. Grifth et al. synthesized benzimidazole derivatives as se-
lective CoA Carboxylase inhibitors for the treatment of diabetes.
Compound 216 was found to be most potent agent for the treat-
ment of type 2 Diabetes mellitus (T2DM) [337]. Saify et al. syn-
thesized various benzimidazole based analogues and evaluated
them for urease inhibitory activity. Compound 217 was found to
exhibit maximum activity. SAR studies indicated that the activity
depends on the inductive and mesomeric effects. The difference in
activity might be due to number as well as nature of the sub-
stituents [338]. Kwak et al. designed and synthesized a series of
aminobenzimidazole and assessed them for anti-obesity and anti-
diabetic activity. Compound 218 was found to have most active
in vitro activity toward human and mouse DGAT-1, good selectivity
toward DGAT-2 [339]. Vlahakis et al. synthesized a novel series of 1-
746 W. Akhtar et al. / European Journal of Medicinal Chemistry 126 (2017) 705e753
(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole.
Amongst them, compound 219 displayed selective inhibition of
heme oxygenase-2 activity [340]. Amongst various benzimidazole
derivatives developed by Lee et al., compound 220 elicited good
diacylglycerol acyltransferase inhibitory activity with IC50 value of
4.4 mM [341]. Hua et al. synthesized a series of 2-Phenylamino-6-
cyano-1H-benzimidazoles and evaluated their casein kinase 1
gamma (CK1g) inhibitory potential. Amongst the synthesized
compounds, compound 221 was reported as a remarkable kinase
inhibitor [342].
3. Conclusion
Benzimidazole, nitrogen containing bicyclic heterocyclic can be
found in numerous therapeutically used agents. There has been an
escalating interest in the development of such compounds target-
ing different diseased conditions. There are a number of challenges
being faced by scientists in the development of compounds bearing
this moiety. A number of clinnically used drugs having benzimid-
azole are in the form of prodrugs like omeprazole, rabeprazole,
pantoprazole and lansoprazole. Thereby, requiring a bit more time
for onset of action. This demands the scientists to engage them-
selves in the development of active form of drugs with this moiety.
This review highlights the current status of this valuable moiety in
the development of novel drug molecules by a medicinal chemist.
The review also covers a brief description of SAR explored by
different scientists which will act as an imperative aid for other
researchers planning to work on development of benzimidazole
based compounds on a common platform.
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