Shrivastava 2017

Arch. Pharm. Chem. Life Sci.
2017, 350, e1700040

ARCH PHARM Archiv der Pharmazie
Review Article
Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches

and Structure–Activity Relationship
Neelima Shrivastava, Mohd. Javed Naim, Md. Jahangir Alam, Farah Nawaz, Shujauddin Ahmed,
and Ozair Alam
Faculty of Pharmacy, , Department of Pharmaceutical Chemistry, Jamia Hamdard, New Delhi, India
Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth
having the potential to invade or spread to other parts of the body. Benzimidazole is an organic
compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion
of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged
structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in
six deaths is due to cancer around the globe, accounting for 8.8 million deaths of which 70% of the
cases were from low- and middle-income countries. In the efforts to develop suitable anticancer
drugs, medicinal chemists have focussed on benzimidazole derivatives. This review article covers the
current development of benzimidazole-based anticancer agents along with the synthetic approaches
and structure–activity relationships (SAR).
Keywords: Alkylating agents / Anticancer / Benzimidazole / Topoisomerase inhibitors / Tubulin inhibitors

Received: February 1, 2017; Revised: April 22, 2017; Accepted: April 25, 2017
DOI 10.1002/ardp.201700040
Introduction a mutation in normal cells [1, 2]. Glutamic acid derivatives,

curcumin-I Knoevenagel’s condensates and their Schiff’s bases
Cancer has now become the disease most urgently to be and platinum compounds were reported to show anticancer
solved because of its incidence and high mortality rate round potential [3–5]. Different kinds of cancer which affect various
the globe. Discovering novel effective anticancer drugs with organs are carcinoma, sarcoma, lymphoma or leukaemia.
fewer side effects is critically important. There are many Thalidomide which was earlier withdrawn from market due
factors which can cause cancer, but cancer is mostly caused by to its teratogenic effects was later approved for treating
metastatic prostate cancer, multiple myeloma, Kaposi’s
sarcoma [6]. The magnitude of cases due to cancer in the
Indian subcontinent is increasing at an alarming rate due to
Correspondence: Dr. Ozair Alam, Faculty of Pharmacy,
underrated living standards and medical facilities with lung
Department of Pharmaceutical Chemistry, Jamia Hamdard, cancer topping the list whereas in the world it has appeared as
Hamdard University, New Delhi 110062, India. a big blow to the humanity. In the recent years, nanotech-
E-mail: dr.ozairalam@gmail.com, oalam@jamiahamdard.ac.in nology is being exploited to give nano anticancer drugs with a
Fax: þ91 11 26059663 targeted approach [7–11]. Multiple previous reports have
suggested that benzimidazole is the most prominent hetero-
Abbreviations: ADP, adenine dinucleotide phosphate; A-549, cycle having good cytotoxic properties against different types
adenocarcinomic human alveolar basal epithelial cell line; BRCA1,
of cancer cell lines. An important example is nocodazole (NSC-
breast cancer gene 1; BRCA2, breast cancer gene 2; CA-4,
combretastatin; DHFR, dihydrofolate reductase; DHODH, dihy- 238189) which exerts its effects by interfering with the
droorotate dehydrogenase; DNA, deoxyribonucleic acid; DU-145, polymerisation of microtubules [12]. Nocodazole is a common
prostate cancer cell lines; EBV-EA, Epstein-Barr virus-early- inhibitor of various cancer-related kinases which includes
antigen; EGFR, epidermal growth factor receptor; HeLa, Henrietta AB1, C-KIT, BRAF, MEK-1, MEK-2 and MET [13]. Others are
Lacks cell lines; IC50, half maximal inhibitory concentration; methyl-2-benzimidazole carbamate (carbendazim, FB642)
MCF-7, breast cancer cell lines; mM, millimolar; MT, microtubules; which inhibits microtubule function resulting in apopto-
NADPH, nicotinamide adenine dinucleotide phosphate; PALB2,
sis [14]. In vitro FB642 demonstrated potent anti-tumour
partner and localizer of BRCA2; PARP, poly(ADP ribose); PTKs,
protein tyrosine kinase; PTP, protein tyrosine phosphatases; SAR, activity against both the murine B16 melanoma and human
structure–activity relationship; SiHa, human cancer of cervix cell HT-29 colon carcinoma cell lines [15] and veliparp (ABT-888), a
lines; Topo-I, topoisomerase-I; Topo-II, topoisomerase-II. potent anticancer drug acting as a poly(ADP ribose)
ß 2017 Deutsche Pharmazeutische Gesellschaft www.archpharm.com (1 of 80) e1700040

Arch. Pharm. Chem. Life Sci. 2017, 350, e1700040
N. Shrivastava et al.
Figure 1. Different targets of benzimidazole as

anticancer agents.
Figure 2. Benzimidazole scaffold-containing

anticancer drugs.

Benzimidazole Scaffold as Anticancer Agent
Table 1. Patents on benzimidazole as anticancer agents.

S. no. Patent no. Patent date Inventors Description
WO2014202763 24 Dec 2014 Alain Moussy, Abdellah Benzimidazole derivatives as
1
A1 [26] Benjahad, Claire Schalon, selective protein kinase
Didier Pez, Emmanuel inhibitors
Chevenier, Franck
Sandrinelli, Jason Martin,
Willy Picoul
2 WO2010096314 26 Aug 2010 Alessandro Boezio, Alan C. Indole/benzimidazole
A1 [27] Cheng, James R. Coats, compounds as mTOR kinase
Katrina W. Copeland, Russell inhibitors
Graceffa, Jean-Christophe
Harmange, Hongbing
Huang, Daniel La, Philip R.
Olivieri, Emily A. Peterson,
Laurie Schenkel
3 WO2008051533 2 May 2008 Kazuyoshi Aso, Michiyo Benzimidazole compounds
A2 [28] Mochizuki, Takuto Kojima,
Katsumi Kobayashi, Scott
Alan Pratt, Albert Charles
Gyorkos, Christopher Peter
Corrette, Suk Young Cho
4 WO2002068407 6 Sep 2002 Kazuhisa Takayama, Benzimidazole compound
A1 [29] Takenori Kimura, Naoyuki
Masuda, Ryo Naito,
Yoshinori Okamoto, Yuji
Koga, Yohei Okada, Makoto
Takeuchi
5 US6310082 30 Oct 2001 Roger J. Griffin, Alan H. Benzimidazole compounds
B1 [30] Calvert, Nicola J. Curtin,
David R. Newell, Bernard T.
Golding
polymerase (PARP) inhibitor [16] which is targeted against

breast cancer cell lines. Different benzimidazole anticancer
targets and marketed drugs are mentioned in Figs. 1 and 2
and the patents regarding the same are listed in Table 1 [17].
Heterocycles play a central role in the field of medicinal as
well as in organic chemistry. Nitrogen heterocycles exhibit
diverse pharmacological activities due to similarities with
many natural and synthetic molecules. Due to this structural
similarity, they can easily interact with biomolecules of living
systems [18]. 5-Flourouracil and methotrexate are some
marketed heterocyclic anticancer drugs whereas vinblastine
and vincristine are some natural products being used as
anticancer drugs [19]. Benzimidazole, a moiety which came in
picture in 1950s, is bicyclic in nature and consists of fusion of
benzene to the 4,5-positions of the imidazole ring [20–23]. It is
also known by other names such as benziminazole or
benzoglyoxaline. The resonance in benzimidazole shows its
amphoteric nature and denotes that electrophilic attack will
be either at N-1 or in the benzene ring; nucleophilic attack to
C-2 position is predicted followed by tautomerization at Figure 3. Benzimidazole scaffold showing numbering, reso-
H-atom which is attached to N-1 position. Due to this property nance and tautomerism.

Scheme 1. Synthesis of 5-substituted-4(1H-benzimidazole-2-yl)

phenol derivatives.
Scheme 3. Synthesis of 1H-benzimidazole derivatives.

of tautomerism in benzimidazole some derivatives which
appear at first to be isomers are in reality tautomers [24].
Benzene ring which is present in 1H-benzimidazole functions
as electron attracting groups on imidazole and thereby
decreases imidazole’s electronic density which plays an camptothecins stabilise the cleavable complexes present in
important role in chemical interaction having varied biologi- DNA relegation and induce lethal DNA strand breaks [34].
cal activities and thus are of great scientific interest nowadays Alpan et al. [35] synthesised 1-H-benzimidazole derivatives
(Fig. 3) [25]. (Scheme 1) and evaluated them for their effects on
mammalian type 1 DNA topoisomerase activity by using
in vitro plasmid supercoil relaxation assays. Compound 4b
(5-methyl-4-(1H-benzimidaozle-2-yl))phenol showed potent
Pharmacological and synthetic profiles of Topo-I inhibitory activity as compared to camptothecin. Ramla
benzimidazole derivatives et al. [36] worked on new benzimidazole derivatives
(Schemes 2 and 3) and biologically characterised them for
Topoisomerase-I (Topo-I) inhibitors their inhibitory activity against the Epstein-Barr virus-
Topoisomerases are the enzymes that help in regulation of early-antigen (EBV-EA) showing most active compounds i.e.
overwinding or underwinding of deoxyribonucleic acid 9d, 8a and 9e as compared to control experiment with butyric
(DNA) [31]. Topoisomerase inhibitors are agents that interfere acid plus TPA (12-o-tetradecanoylphorbol-13-acetate). Gao
with the action of topoisomerase enzymes (Topo-I and -II) et al. [37] carried out a new series of novel benzimidazole
which controls the changes in DNA structure [32, 33]. Human acridine derivatives (Scheme 4) to be new DNA-targeted
Topo-I is an essential enzyme that relaxes DNA supercoiling compounds and screened for anti-proliferative activities.
during replication and transcription. Topo-I inhibitors such as Compound 21l with IC50 ¼ 8.11 mM displayed highest activities
Scheme 2. Synthesis of benzimidazole derivatives.

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Archiv der Pharmazie
Scheme 4. Synthesis of novel benzimidazole acridine derivatives.

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Table 2. SAR of topoisomerase-I inhibitors.

S. no. SAR

Scheme 5. Synthesis of bis(benzimidazole) derivatives.
complexes. These agents create a lesion that includes

against both K562 and HepG-2 cells when compared to DNA strand breaks and proteins which are covalently
colchicine and imatinib (Table 2). bound to DNA and are known as Topo-II poisons.
(b) The second class of agents inhibit Topo-II catalytic activity
Topoisomerase-II (Topo-II) inhibitors but do not generate increase in the levels of Topo-II
Topo-II are the enzymes which have the ability to cut both the covalent complexes. This class is known as catalytic
strands of a double-stranded DNA molecule to pass another inhibitors as they are thought to kill cells via elimination
portion of the duplex via cut and reseal it in a process that uses of the essential enzymatic activity of Topo-II [39].
Adenosine Tri Phosphate (ATP) [38]. Topo-II inhibitors act by
two different ways as per the drug target:
(a) The first class includes agents like etoposide which Huang et al. [40] discovered and evaluated structurally
lead to increase in the levels of Topo-II DNA covalent similar bis(benzimidazole) derivatives (Schemes 5–7) of
Scheme 6. Synthesis of 2(2-hydroxyphenyl)-3H-benzo[d]imidazole-4-carboxylic acid derivative.

Scheme 7. Synthesis of methyl 2-(2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-4-yl)-1H-benzo[d]imidazole-4-carboxylate derivative.
Table 3. SAR of topoisomerase-II inhibitors.

S. no. SAR

which compounds 43 (IC50 ¼ 9.6 mM), 45 (IC50 ¼ 6.6 mM) and They are non-specific in nature. Upon interaction with the
46 (IC50 ¼ 9.2mM) exhibited potent anticancer activity DNA bases, they inhibit DNA replication thus forming the
whereas compound 44 is more potent than UK-1 against basis for the anti-tumour effects [41].
human lung (A-549) and epithelial (HeLa) carcinoma cell Demirayak et al. [42] synthesised some 1-methylene-2,3-
lines (Table 3). diaryl-1,2-dihydropyrazino[1,2-a]benzimidazole and some 1-
(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives
DNA intercalation and alkylating agents and screened them for anticancer activity (Schemes 8
DNA alkylators also known as cross-linkers are most active and 9). Compound 52o was found to be most potent against
agents for the management of cancer. They have the property leukaemia cell lines using melphalan and cis-diaminodichlor-
of high chemical reactivity; all alkylating agents form covalent oplatinum as standard compounds. He et al. [43] designed,
linkages with macromolecules having nucleophilic centres. prepared and characterised cis-dichloro platinum complexes
Scheme 8. Synthesis of 1-methylene-2,3-diaryl-1,2-dihydro pyrazino[1,2-a]benzimidazole derivatives.

Scheme 9. Synthesis of 1-(2-aryl vinyl)-3-aryl pyrazino[1,2-a]benzimidazole derivatives.
containing biologically relevant 2-pyridylbenzimidazole, oxa- Fu et al. [48] synthesised and characterised a new ternary
zole and thiazole derivatives (Schemes 10 and 11) and copper(II) complex 131 (Schemes 26 and 27) with IC50 ¼ 5 mM
screened them against cis-platin sensitive and cis-platin exhibiting desired binding affinity to HSA. Kumar et al. [49]
resistant cells. Compound 60a showed excellent results. reported the synthesis of novel cationic Ru(II), Rh(III) and Ir(III)
LeSann et al. [44] described a new method for the synthesis complexes containing cyclic p-perimeter and 2-aminophenyl
of symmetric bis-benzimidazoles having 2-aryl moieties along benzimidazole ligands and evaluated for anticancer activity
with the synthesis of novel hybrid molecules and their in vitro against cervical cancer (SiHa) cell line (Scheme 28). Compound
activities were tested against five cancer cell lines of which 133(5) was found to be most potent having IC50 value of
compound 83b was found to be most potent against 6.14 mM (Table 4).
chlorambucil as reference drug (Schemes 12–15). Kamal
et al. [45] prepared C-8 linked PBD-benzimidazole conjugates Androgen receptor antagonists
(Schemes 16 and 17) of which compound 98a exhibited Androgen receptor (AR) is a type of nuclear receptor which
potential anticancer activity with LC50 values ranging from gets activated by binding either of the androgenic hormones,
0.01 to 50 mM in comparison to DC-81 as reference drug. Gellis testosterone or dihydrotestosterone, in the cytoplasm. AR
et al. [46] synthesised new benzimidazole-4,7-diones substi- antagonists bind to the receptor with higher affinity thereby
tuted at second position (Schemes 18–24) and evaluated for preventing nuclear translocation and DNA binding, and
cytotoxicity against colon, breast and lung cancer cell lines of induce apoptosis without agonist activity. Androgenic recep-
which dimer 119 possessed excellent cytotoxicity with IC50 tor is in direct regulation of gene transcription. The binding of
¼ 3 1 mM using mitomycin-C as the reference drug. Gowda an androgen to the ARs will result into conformational
et al. [47] carried out the synthesis of novel (1-4-methox- changes in the receptor which in turn causes dissociation of
yphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives heat shock proteins, then transportation from the cytosol into
and their precursors as potential chemotherapeutic agents the cell nucleus and dimerisation [50–53].
(Scheme 25). Compound 124a was found to be potent anti- Ng et al. [54] reported the synthesis of 5,6-dichloro-
leukaemic agent (IC50 ¼ 3 mM) against K562 and CEM cell lines. benzimidazole derivatives as selective AR antagonists
Scheme 11. Synthesis of 2-pyridyl benzimidazole, oxazole and

Scheme 10. Synthesis of cis-dichloroplatinum complexes. thiazole derivatives.

(Schemes 29 and 30). Compound 136 with ID50 ¼ agents [56]. Drugs that inhibit PARP-1 cause multiple double
0.15 mg/day emerged out as the most potent compound in strand breaks to form in this way and in tumours with breast
comparison to bicalutamide. Ng et al. [55] prepared novel 2- cancer gene 1 (BRCA1), breast cancer gene 2 (BRCA2) or
(2,2,2)-trifluoroethyl-benzimidazoles scaffold (Schemes partner and localiser of BRCA2 (PALB2) mutations, these
31–33) among which compound 151 showed potent andro- double strands break once been formed cannot be effectively
genic antagonistic activity (ID50 ¼ 0.03–0.11 mg/day) as com- repaired and finally lead to cell death [57, 58].
pared to bicalutamide (Table 5). White et al. [59] synthesised new derivatives of
2-arylbenzimidazole-4-carboxamides and screened for anti-
PARP inhibitors cancer potential and found to be potent inhibitors of
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme PARP and able to act as resistance modifying agents
which plays an important role in many cellular processes (Schemes 34–37). Compound 173 was found to be most
including modulation of chromatin structure, transcription, potent with Ki ¼ 6.0 nM as compared to 3-aminobenzamide
replication, recombination and DNA repair. PARP inhibitors (Ki ¼ 3100 nM) as the standard drug. Zhu et al. [60] synthesised
may increase the tumour sensitivity to DNA-damaging a novel series of PARP inhibitors containing a quaternary
Scheme 12. Synthesis of bis-benzimidazoles having 2-aryl moieties.

Scheme 13. Synthesis of N-(3-(dimethyl amino)propyl)-4-(5-methyl-3H-indole-2-yl)benzenamine derivatives.
methylene-amino substituent at C-2 position of the benz- lines with IC50 values 73.7 4.3 mM, 60.9 6.1 mM,
imidazole (Scheme 38). Two optimised inhibitors 185a and 53.9 2.2 mM and 175.9 4.8 mM (Table 6).
185b showed excellent intrinsic potency against PARP-I as
compared to temozolomide. Tong et al. [61] disclosed distinct Protein tyrosine kinase inhibitors
class of inhibitors possessing unsaturated heterocycles Protein tyrosine kinases (PTKs) are a group of enzymes which
appended to the benzimidazole core (Schemes 39–45). play a main role in various cellular processes. In cancer cells,
Compounds 203 and 222 exhibited good pharmacokinetic some protein kinases are activated and drive tumour growth
properties and potent oral in vivo efficacy in potentiating the and progression. In many proteins, protein kinases catalyse
cytotoxic agent temozolomide (TMZ) in a mouse xenograft the phosphorylation of tyrosine and serine/threonine
model. Pantic et al. [62] prepared three new ruthenium(II)- residues [63]. PTKs are classified as epidermal growth factor
arene halido complexes and evaluated them for cytotoxic receptor (EGFR) or non-receptor kinases. EGFR belongs to
activity against human cancer cell lines (Scheme 46). Complex
225a exhibited highest and selective cytotoxicity towards
cervical carcinoma (HeLa), breast carcinoma (MDA-MB-231),
myelogenous leukaemia (K562) as well as in one normal
human foetal lung fibroblast cell line (MRC-5) tumour cell
Scheme 14. Synthesis of 4-(6-methyl-1H-benzo[d]imidazole-2- Scheme 15. Synthesis of bis-(4-[3-chloropropanamide]phenyl)-

yl)phenol derivatives. 5,5-bis-1H-benzimidazole derivatives.

Scheme 16. Synthesis of C-8 linked PBD-benzimidazole conjugates.
Scheme 17. Synthesis of novel PBD-benz-

imidazole conjugates.

Scheme 18. Synthesis of benzimidazole-4,7-diones.
(Schemes 47–49). Compound 226 was found to be more

cytostatic and cytotoxic than 242. Yadav et al. [68] reported
a series of new benzimidazole analogues (Scheme 50).
Compound 247 was found to be most potent with IC50
0.049 0.005 against EGFR-tyrosine kinase. Lukowska-
Chojnacka et al. [69] synthesised novel polybrominated
benzimidazole derivatives (Scheme 51) and evaluated them
Scheme 19. Synthesis of new benzimidazole-4,7-diones substi- for anticancer and proapoptotic activity against acute
tuted at 2nd position.
lymphocytic leukaemia (CCRF-CEM) and breast cancer cell
lines (MCF-7). Compound 248a with Ki ¼ 1.03 0.24 mM as a
new selective inhibitor of rhCK2 with 20-fold better
transmembrane growth factor receptor PTKs [64, 65]. They proapoptotic activity than parental compounds (TBBi)
interfere with specific cell signalling pathways and thus allow (Table 7).
target-specific therapy for selected malignancies [66].
Labarbera and Skibo [67] synthesised imidazoquinoxali- Protein tyrosine phosphatase inhibitors
none derivatives which are benzimidazole analogues of Protein tyrosine phosphatases (PTPs), also known as tyrosine
indole-based marine natural products called makaluvamins protein phosphatases, are a group of enzymes that remove
Scheme 20. Synthesis of 2-(chloromethyl)-1-

methyl-4,5,dichloro-1H-imidazole cyclohexa-
2,5-diene-1,4-dione.
Scheme 21. Synthesis of 2-(bromomethyl)-1-methyl-4,5,dichloro-1H-imidazole cyclohexa-2,5-diene-1,4-dione.

Scheme 22. Synthesis of 1,5,6-trimethyl-2-(2-nitropropan-2-yl)-1H-benzo[d]imidazole-4,7-dione derivatives.
Scheme 23. Synthesis of 1,5,6-trimethyl-2-(2-meth-

ylprop-1-enyl)-1H-benzo[d]imidazole-4,7-dione.
phosphate groups from phosphorylated tyrosine residues on cancer cell lines (A549, CH1(PA-1) and SW480) followed by
proteins. They are also involved in the regulation of a number comparing activity of free ligand and of vanadyl acetylacet-
of cellular processes such as cell differentiation, communica- onate and sodium orthovanadate. Complex 253 significantly
tion, etc. [70, 71]. inhibited the PTPs 1B (Table 8).
Habala et al. [72] synthesised four new complexes of group
12 metals along with vanadyl bound to ligand and the Dihydrofolate reductase inhibitors
cytotoxicity of complexes was tested in vivo against three Dihydrofolate reductase (DHFR) is an enzyme that reduces
dihydrofolic acid to tetrahydrofolic acid by the use of
nicotinamide adenine dinucleotide phosphate (NADPH)
as electron donor [73]. Folate is needed for the function
of dihydrofolate reductase. The process of inhibition
is of therapeutic advantage as it can be used as cancer
chemotherapy, preventing cancerous cells from dividing
[74, 75].
Singla et al. [76] synthesised triazine-benzimidazole hybrids
and evaluated their inhibitory activities over 60 human
tumour cell lines (Schemes 52–54). Compound 265 with
Scheme 24. Synthesis of 2-(chloromethyl)5-(2-(chloromethyl)-1- IC50 ¼ 1.05 mM was depicted as the most active member of
methyl-4,7-dioxo-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-5- mammalian dihydrofolate reductase (DHFR) inhibitors
yl)-1-methyl-1H-benzo[d]imidazole-4,7-dione. (Table 9).

Scheme 25. Synthesis of novel 1-(4 methoxyphenethyl)-1H-1benzimidazole-5-carboxylic acid derivatives.
Microtubule inhibitors Taher et al. [79] reported synthesis of some conjugates by

Microtubules (MTs) are dynamic filamentous structures of a Schiff base reaction (Scheme 55). Compounds 285b, 285d
eukaryotic cytoskeleton. They form mitotic spindle during cell and 285g possessed significant anti-proliferative activity
division. Disturbing those leads to mitotic arrest and against human breast carcinoma cell lines (MCF-7cells) as
ultimately cell death. MTs and their building blocks ab compared to doxorubicin with IC50 of 24.95, 26.36 and
tubulin are currently being one of the best targets in 22.59 nM. Wang et al. [80] synthesised benzimidazole-2-
anticancer chemotherapy [77]. A large number of agents urea derivatives (Scheme 56) in which compound 293o
which are mostly obtained from natural sources bind to emerged as the most potent b-tubulin inhibitor by
tubulin and/or microtubules, altering microtubule polymeri- inhibiting NCI-H460 spindle formation and cell cycle arrest
sation and dynamics in diverse ways [78]. at G2/M phase at 0.10 mM with IC50 value of 0.04 0.02 mM
against taxol and colchicine as the standard drugs. Guan
et al. [81] synthesised benzimidazole carbamates bearing
indole moieties (Scheme 57) and assayed them against
human cancer cell lines for their anti-proliferative and
anti-tubulin activity. Compound 300a was the most potent
derivative with IC50 values of 0.098 0.002, 0.15 0.05 and
0.13 0.07 mM (SGC-7901, A-549 and HT-1080) using
Scheme 26. Synthesis of new ternary copper(II) complex. nocodazole as a positive control. Also compound 300a

Scheme 27. Synthesis of copper complexes

linked with benzimidazole ring.
showed similar binding mode to that of nocodazole at the against HCT116, A2780 and HepG2 cancer cell lines as
colchicine site of tubulin and inhibits tubulin polymerisa- compared to standard drug CK0106023 with IC50 values of
tion. with IC50 ¼ 3.6 and 2.3 mM. Kamal et al. [82] syn- 1.20, 3.10 and 2.11 mM for 327e and 1.32, 3.50 and 2.34 mM
thesised imidazo[1,5-a]pyridine–benzimidazole hybrids for 327k followed by IC50 values 0.0009 and 1.22 mM and
(Scheme 58) and assayed against 60 cancer cell lines in 0.0010 and 1.37 mM against kinesin spindle protein (KSP)
which compound 307l exhibited significant cytotoxicity and Aurora A kinase for the same compounds. Kamal
with GI50 values ranging from 0.43 to 7.73 mM. Also it et al. [85] synthesised new benzimidazole-linked pyrrolo-
exhibited inhibition of tubulin polymerisation upto benzodiazepine conjugates (Schemes 64–66) among which
71.27% with IC 50 values 1.71 mM against nocodazole compound 341c showed promising in vitro cytotoxicity
(1.75 mM) as the standard drug. Abdullah et al. [83] carried against a number of human cancer cell lines. Stepanov
out the synthesis of new benzimidazole derivatives as et al. [86] synthesised a series of 4(1H-benzo[d]imidazole-
potential dual inhibitors for PARP-1 and dihydroorotate 2-yl]-furazan-3-amines (BIFAs) (Schemes 67 and 68) and
dehydrogenase (DHODH) enzymes (Schemes 59 and 60). evaluated for their anti-proliferative effects in sea urchin
Compounds 318c and 316b showed most potent results embryo model and in cultured human cancer cell lines.
against veliparib and brequinar as reference inhibitors. El- Compound 406 was found to be the most active molecule
All et al. [84] described the synthesis of anticancer (GI 50 ¼ 0.24 mM) in reference to colchicine and vinblastine
compounds, i.e. thiazole[3,2-a]pyrimidine derivative bear- sulphate as reference drugs. Ahmed Kamal et al. [87]
ing benzimidazole moiety (Schemes 61–63). Compounds worked on a series of benzimidazole-oxindole conjugates
327e and 327k showed potent dual inhibitory activity and evaluated them for their cytotoxic potential against
Scheme 28. Synthesis of platinum complexes containing benzimidazole derivatives.

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Table 4. SAR of DNA intercalation and alkylating agents.

S. no. SAR
(Continued)

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Table 4. (Continued)
S. no. SAR
3
(Continued)

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S. no. SAR

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Scheme 29. Synthesis of 5,6-dichloro-benzimidazole derivative.
Scheme 30. Synthesis of 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-1-(ethylthio)propan-2-ol.
Scheme 31. Synthesis of novel 2-(2,2,2)-trifluoroethyl-benzimidazole scaffold.

Scheme 32. Synthesis of 2-(5,6-dichloro-1H-benzimidazole[d]imidazol-2-yl)-1,1,1-trifluoro-4-(2,2,2-trifluoroethylthio)butan-2-ol

derivatives.
human breast cancer cell line (MCF-7) (Scheme 69). et al. [90] reported 2-aryl-1,2,4-oxadiazolo-benzimidazole
Compound 420c with IC50 value 1.12 mM is found to be conjugates (Scheme 72) and evaluated against 60 cancer
most potent against nocodazole as the standard drug. cell lines for anti-proliferative activity. Compounds 437l
Kamal et al. [88] reported the synthesis of arylpyrazole- and 437x showed most potent results with GI50 values in
linked benzimidazole conjugates (Scheme 70) and evalu- the range of 0.79–28.2 mM at five dose concentration assay
ated for their ability to inhibit the growth of cancer cells (0.01, 0.1, 1, 10 and 100 mM). Also these compounds
against HepG2 (liver carcinoma), A549 (lung cancer), MCF- showed 55.6 and 52.1% inhibition of microtubule assem-
7 (breast cancer), HeLa (cervical cancer) and DU-145 bly with IC50 values of 1.5 and 1.8 mM as compared to
(prostate cancer) cancer cell lines against nocodazole nocodazole (1.7 mM). Ashraf et al. [91] synthesised cis-
and CA-4 as standard drugs. Compound 426 is the most restricted benzimidazole derivatives (Scheme 73) and
potent derivative with IC 50 value of 10 mM. Wang evaluated for their antiproliferative activity against
et al. [89] designed and synthesised a series of 1-benzene cancer cell lines. Compounds 442c and 442l demonstrated
acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives an anti-proliferative effect with GI 50 ¼ 0.06 0.001 mM,
(Scheme 71) and evaluated them as tubulin polymerisa- 0.26 0.02 mM, 0.13 0.01 mM and 0.18 0.03 and
tion inhibitors. Compound 432f showed most potent 0.04 0.001 mM, 0.079 0.001 mM, 0.091 0.002 mM and
results with IC50 ¼ 1.5 mM and anti-proliferative activity 0.052 0.001 mM which was found to be comparable
of GI 50 ¼ 2.4, 3.8 and 5.1 mM against A549, HepG2 and and superior to that of combretastatin A-4. Shaik
MCF-7 cell lines as compared to colchicine and CA-4. Kamal et al. [92] synthesised imidazo[2,1-b]thiazole-linked
Scheme 33. Synthesis of 2-aryl benzimidazole-4-carboxamide derivatives.

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Table 5. SAR of androgen receptor antagonists.

S. no SAR

Scheme 34. Synthesis of 2,3-diamino benzoic acid, methyl 2,3-diaminobenzoate and 2,3-diaminobenzamide derivative.
Scheme 35. Synthesis of 3H-benzo[d]imidazole-4-carboxamides.
Scheme 36. Synthesis of 1H-benzimidazole-4-carboxamide derivatives.

triazole conjugates (Scheme 74) and assayed them against

HeLa, DU-145, A549, MCF-7 and HepG2 cell lines.
Compound 445h was the most potent derivative with
IC50 values of 2.690, 3.090, 0.788, 1.013 and 5.821 mM
against doxorubicin as the standard drug and caused cell
cycle arrest at G2/M phase (Table 10).
Scheme 37. Synthesis of triisopropylsilyloxymethyl derivatives.
Scheme 38. Synthesis of PARP inhibitors containing quaternary methylene-amino substitutent at C-2 position.
Scheme 39. Synthesis of benzimidazole based PARP-I inhibitors.

Scheme 40. Synthesis of PARP inhibitors possessing unsaturated heterocycles appended to the benzimidazole core.
Scheme 41. Synthesis of 2-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3H-benzo[d]imidazole-4-carboxamide.

Scheme 42. Synthesis of 2-(4-(5-thioxo-4,5-

dihydro-1,2,4-oxadiazol-3-yl)phenyl)-3H-
benzo[d]imidazole-4-carboxamide.
Scheme 43. Synthesis of 2-(4-isoxazol-5-yl)phe-

nyl)-3H-benzo[d]imidazole-4-carboxamide.
Scheme 44. Synthesis of 2-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)-3H-benzo[d]imidazole-4-carboxamide derivative.

CNS-SF-268 cancer cell lines (Scheme 76). Among the

synthesised compounds no significant anticancer activity
was observed with any of the tested compounds. Abdel-
Aziz et al. [98] synthesised novel thiazolo[3,2-a]benzimid-
azole derivatives (Scheme 77). Compound 463 was found
to be strongly cytotoxic against both colon carcinoma cells
(HCT-116) and hepatocellular carcinoma cells (Hep-G2)
while 469b showed specific cytotoxicity only against colon
carcinoma cells as determined through MTT assay using
paclitaxel as the reference drug with an IC50 value of 710
and 825 nM against HCT-116 and Hep-G2 cell lines.
Shaharyar et al. [99] reported the synthesis of pyrazoline
bearing benzimidazole derivatives (Scheme 78) of which
compound 476f 2-[5-(3,4-dimethoxyphenyl)-1-4,5-dihy-
dro-1H-3-pyrazolyl)-1H-benzimidazole was found to be
most potent when analysed at National Cancer Institute,
USA. Romero-Castro et al. [100] prepared a series of six 2-
aryl-5(6)-nitro-1H-benzimidazole derivatives (Schemes 79
and 80) as potent anticancer agent. Compound 484 was
regarded as the most potent anticancer agent having
IC50 ¼ 22.2 mM whereas compound 479c displayed best
PARP inhibition with an IC 50 ¼ 0.05 mM. Ravindra
Scheme 45. Synthesis of 2-(4-pyridin-2-yl)phenyl)-3H-benzo[d] et al. [101] synthesised a new series of Mannich bases
imidazole-4-carboxamide derivative. (Scheme 81) and evaluated them for anticancer activity.
Compound 488f was found to be potential lead as a novel
anticancer agent with IC50 values of 2.8 0.031,
b-Glucuronidase inhibitors 3.60 0.043 and 3.82 0.1 mM against HepG2, MCF-7
7b-Glucuronidase acts as glycoside hydrolase enzyme which and HeLa cell lines using YM-201627 as standard control.
eliminates large number of toxic compound from the body as Demirayak et al. [102] synthesised 1,3-diarylpyrazino[1,2-
glucuronides. When the amount of b-glucuronidase is a]benzimidazole derivatives (Scheme 82) and their anti-
increased, it will lead to occurrence of colon carcinoma; cancer activities were studied against melphalan and
therefore inhibition of b-glucuronidase enzyme is effective in cisplatin as standard compounds. Compounds 493c and
preventing various diseases [93–95]. 493h bearing methoxy group were found to be most
potent. Nofal et al. [103] reported novel benzimidazole
Taha et al. [96] subjected 25 benzimidazole derivatives with derivatives (Scheme 83) that incorporated different
reported activity against b-glucuronidase inhibitors heterocycles of anticancer activity and were evaluated
(Scheme 75). Compound 448 was found to be most potent as anticancer agents in HepG2 and PC12 cells. Compound
with IC50 ¼ 48.4 1.25 mM as compared to standard drug D- 499a having IC50 ¼ 2.4 mM exhibited high potency against
saccharic acid 1,4-lactone with IC50 ¼ 48.4 1.25 mM (Table 11). HepG2 and PC12 cells. Compounds 495c and 495e with
IC50 ¼ 0.103 and 5 mM showed high potency against PC12
Miscellaneous anticancer agents cells. Husain et al. [104] synthesised benzimidazole
Rida et al. [97] reported the synthesis of novel benzofuran clubbed with oxadiazole ring systems hybrid with the
and related benzimidazole derivatives and evaluated aim to produce promising anticancer agents (Scheme 84).
them for anticancer activity against MCF7, NCI-H460 and In vitro anticancer activities of synthesised compounds
Scheme 46. Synthesis of new ruthenium(II)

arene halide complexes.

ARCH PHARM
Table 6. SAR of PARP-poly (ADP-ribose) inhibitors.

S. no. SAR
(Continued)

S. no. SAR
3
were screened against NCI 60 human cell lines panel of Sivaram et al. [107] synthesised a series of gold(I) and
which compound 508j exhibited significant growth inhi- gold(III) complexes bearing benzimidazole and pyrazole
bition. Rashid et al. [105] synthesised benzimidazoles derivatives (Schemes 88 and 89) and characterised them
derivatives clubbed with other heterocyclic moieties for their anticancer activity against NCI:H1666 non-small
including the oxadiazole nucleus (Schemes 85 and 86). cell lung cancer cell line among which the carbine complex
The title compounds were then screened for their in vitro 524 showed superior activity. Husain et al. [108] reported a
anticancer activity at NCI 60 cell line panel of which novel series of benzimidazole clubbed with fused rings
compound 514l emerged as lead compound. Blaszczak- resulting in hybrid compounds showing promising anti-
Swiatkiewicz et al. [106] synthesised new benzimidazole cancer activities (Schemes 90 and 91). In vitro anticancer
derivatives (Scheme 87) and characterised them for activities of synthesised compounds were screened against
anticancer activity against the reference compound NCI 60 cell lines panel of which compound 537h exhibited
tirapazamine. Compounds 517a, 517c and 518a exhibited significant growth inhibition with GI 50 values ranging
potent properties when tested against cells of human from 0.20 to 2.58 mM. Babu et al. [109] prepared a series of
malignant melanoma WM115 with Trypan blue test. novel 2-(3-methylindolyl)benzimidazole derivatives and

ARCH PHARM
Scheme 47. Synthesis of 8-amino-2-methyl-4,5-dihydroimidazo[1,5,4-de]quinoxalin-9-one.
Scheme 48. Synthesis of imidazoquinoxalinone derivatives.

Scheme 49. Synthesis of novel imidazoquinoxalinone derivatives.
Scheme 50. Synthesis of new benzimidazole anlogs.
evaluated them for anticancer activity (Scheme 92).

Compounds 543a–c and 544f showed good anticancer
activity and therefore served as lead molecules in
synthesising new compounds. Abdelgawad et al. [110]
reported the synthesis of a new series of heterocyclic
compounds bearing pyrazole nucleus linked to benzo-
thiazole, benzoxazole or benzimidazole nucleus
(Schemes 93 and 94). Twelve novel compounds 548a–c
and 550a–i were tested for their cytotoxicity against
breast carcinoma (T47D) and human hepatocarcinoma cell
lines (Huh-7) using doxorubicin as the reference drug.
Scheme 51. Synthesis of novel polybrominated benzimidazole Compound 550b showed potent in vitro anti-tumour
derivatives. activity against Huh-7 hepatocarcinoma cell line with

ARCH PHARM
Table 7. SAR of protein tyrosine kinase inhibitors.

S. no. SAR
1

ARCH PHARM
Table 8. SAR of protein tyrosine phosphatase inhibitors.

S. no. SAR
1
Scheme 52. Synthesis of triazine-benzimidazole hybrids.

Scheme 53. Synthesis of 3-benzyl-N-(4-chloroo-6-morpholino-1,3,5-triazin-2-yl)-2-methyl-2,3-dihydro-1H-benzo[d]imidazol-4-

amine derivatives.
Scheme 54. Synthesis of 1-benzyl-N-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-5-amine derivatives.

Table 9. SAR of dihydrofolate reductase (DHFR) inhibitors.

S. no. SAR
1
Scheme 55. Synthesis of 3-(4,5-dihydrothiazol-2-ylamino)-1-(dimorpholinoamino)methyl)indolin-2-one derivatives.

ARCH PHARM
Scheme 56. Synthesis of benzimidazole-2-urea derivatives.
Scheme 57. Synthesis of benzimidazole carbamates bearing indole derivatives.

Scheme 58. Synthesis of imidazo[1,5-a]pyrolidine-benzimidazole hybrids.
IC50 ¼ 16.22 mg/mL. Koppireddi et al. [111] synthesised a ascites tumour (EAT) bearing mice in which 564d exhibited
series of new 3,6-diphenylimidazo[2,1-b]thiazole deriva- potent results. Gurkan-Alp et al. [114] reported a series of
tives (Scheme 95) and evaluated for anticancer activity novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives
against HeLa, MDA-MB-231, A549 and THP1 human cancer (Scheme 98) of which compounds 570, 571 and 574
cell lines. Compound 554j showed significant cytotoxicity exhibited remarkable cytotoxic activity. Varshney
in HeLa cells with IC 50 ¼ 6.5 0.56 mM. Ali et al. [112] et al. [115] carried out the synthesis of novel series of
synthesised a series of novel imidazo[2,1-b]thiazoles hydroxyl and non-hydroxy long chain substituted 1,3,
bearing pyrazole moieties (Scheme 96). Eleven compounds 4-oxadiazole moiety bearing 2-methyl-1H-benzimidazoles
were screened at NCI and their in vitro anticancer (Scheme 99). Compounds 587a,c,d showed excellent
evaluation revealed that compounds 558–560(a) were anticancer activity against Hep3B, MCF7 and HeLa
promising towards CNS SB-75 and renal UO-31 cancer cell cell lines with IC 50 values of 11.10 1.1, 12.40 0.5,
lines when tested against standard drug rapamycin as 11.70 2.9 mM (587a), 14.10 0.8, 12.20 0.7,
standard drug. Roopashree et al. [113] synthesised novel 14.40 1.2 mM (587c) and 13.90 0.8, 11.10 0.7,
bis-benzimidazole derivatives (Scheme 97) and screened 10.60 1.2 mM (587d) against doxorobucin and fluoroura-
them for their anticancer properties of which FDNB act as cil as the standard drugs. Abdel-Aziz et al. [116] reported a
potent anti-proliferative agent (IC 50 > 50 mM) against series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones
HeLa, HCT116 and A549 cells. Also the synthesised and assayed them for anti-proliferative activity against
compounds were additionally evaluated for their in vivo colon HT-29 cancer cell line and inhibition activity towards
anti-tumour and anti-angiogenic properties using Ehrlich cell surface expression of CD133 at 10 mM concentration
Scheme 59. Synthesis of methyl 4,5,6-tri-

methyl cyclohexa-2,4-diene carboxylate
derivatives.

ARCH PHARMArchiv der Pharmazie
Scheme 60. Synthesis of 2(2,3,4-trimethylphenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives.
Scheme 61. Synthesis of thiazole[3,2-a]pyrimidine derivative bearing benzimidazole derivatives.

Scheme 62. Synthesis of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-7-amino 5-(4-nitrophenyl)-8,8 a-dihydro-5H-thiazolo[3,2-1]pyrimi-

dine-6-carboxamide derivatives.
Scheme 63. Synthesis of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine derivatives.
(Scheme 100). Compound 592 with IC50 ¼ 18.83 1.37 mM potential bioactive hybrid, purine-benzimidazole deriva-
emerged as the most potent anti-proliferative agent tives and assayed them against 60 human tumour cell lines
which is almost equipotent to fluorouracil with IC50 at one dose concentration level (Scheme 101). Compound
¼ 15.83 1.63 mM inhibition value of 50.11 4.05% on 596 showed most significant results and again tested at
CD133 expression. Sharma et al. [117] synthesised five dose concentration levels against 60 cell line panel
and showed sensitivity towards colon, CNS and ovarian
cancer with GI50 values of 3.16, 2.00 and 1.36 mM at 10 5
concentration. Compound 596 was found to be 1.25-fold
more potent than 5-fluorouracil with GI 50 ¼ 18.12 mM
(MG-MID) and selective towards Aurora-A kinase inhibi-
tion with IC 50 ¼ 0.01 mM. Nayak et al. [118] reported
compounds 597c and 597p which exhibited significant
anti-proliferative activity against MCF-7 cell lines and
induced mitochondrial mediated (intrinsic apoptotic
pathway) apoptosis. Pett et al. [119] reported diamino
polyamide 598a–c with an alkyl amino group at the N1
Scheme 64. Synthesis of benzimidazole derivatives linked to position of the imidazole/pyrrole ring and assayed for
five membered heterocyclic ring. modulation of topo IIa and inhibition of NF-Y binding.

ARCH PHARM
Scheme 65. Synthesis of new benzimidazole linked pyrrolobenzodiazepine conjugates.
Scheme 66. Synthesis of newer benzimidazole derivativatives linked to pyrrolobenzodiazepines.

Scheme 67. Synthesis of a series of 4-(1H-benzo[d]imidazole-2-yl]furan-3-amines (BIFAs).
Chojnacka et al. [120] synthesized benzimidazole Sharma et al. [123] synthesised (E)-benzo[d]imidazol-2-yl)
and benzotriazole derivatives containing (Scheme 102) methylene)indolin-2-one derivatives and assayed for cyto-
tetrazole moiety through N-alkylation of 5-aryltetrazole toxic activity against prostate (PC-3 and DU-145), breast (BT-
with 4,5,6,7-tetrabromo-1-(3-chloropropyl)-1H-benzimid- 549, MDA-MB-231, MCF-7, 4T1), non-small lung (A549) and
azole and 4,5,6,7-tetrabromo-2-(3-chloropropyl)-2H-benzo- gastric cancer cells (HGC) (Scheme 104). Compound 625
triazole in which compounds 601 and 603 showed most showed most potent cytotoxic activity with IC50 > 50 mM,
potent anticancer results against CCRF-CEM and MCF-7 cell 39.55 2.28 mM, >50 mM, >50 mM, >50 mM, >50 mM,
lines. Nayak et al. [121] reported 2-aryl benzimidazole 41.23 3.82 mM and >50 mM against cancer cell lines using
conjugates and assayed them against MCF-7 cell lines for sunitinib as a reference standard. Perin et al. [124] reported
anticancer activity. Compound 604 (2-(2-ethoxyphenyl)-6- the anti-proliferative and DNA binding properties of a series
methyl-1H-benzo[d]imidazole) emerged as the most potent of 2-amino, 5-amino and 2,5-diamino-substituted
anticancer agent which arrested cell cycle at G2/M phase benzimidazo[1,2-a]quinolones and assessed for anti-prolif-
(26.94 and 45.93% cell accumulation) and inhibited/down- erative activity against colon, lung and breast carcinoma cell
regulated Topo-II activity which finally leads to cell death lines (Scheme 105). Compounds 630a,b were found to be
(apoptosis). Sharma et al. [122] reported benzimidazole- most potent with IC50 ¼ 0.6 0.3 mM, 2 1 mM, 1 0.8 mM
thiazolidinedione hybrids and evaluated their cytotoxic and 0.3 0.08 mM, 0.6 0.2 mM and 0.5 0.04 mM using
property against prostate (PC-3 and DU-145), breast (MDA- doxorubicin and etoposide as the standard drugs. Singla
MB-231) and lung (A549) cancer cell lines (Scheme 103). et al. [125] reported novel triazine-benzimidazole analogs
Compound 618 exhibited promising cytotoxic potential with and assayed them on 60 human cancer cell lines for
IC50 values of 39.87 3.16, 31.41 1.52, 29.18 0.93 and anticancer activity (Scheme 106). Compound 634 was the
11.46 1.46 mM against 5-fluorouracil as the standard drug. most potent derivative with mean growth of 83.19% at one

Scheme 68. Synthesis of of 4-(1H-benzo[d]imidazole-2-yl]-furazan-3-amines (BIFAs).
dose level (10 mM). When assayed at five dose level (0.01– and HepG2 cell lines for growth inhibition assay
100 mM) it showed GI50 value of 31 nM against leukaemia (Scheme 107). Compound 637 was the most potent derivative
cancer cell line and 222 nM against renal cancer cell line against HCT116, MCF7 and HepG2 cell lines with IC50 ¼ 0.062
RXF393. Wu et al. [126] designed and synthesised novel 1.45, 3.64 0.39 and 0.34 0.68 mM as compared to
benzimidazole-2-subsituted phenyl or pyridine propyl ke- 5-fluorouracil (IC50 ¼ 56.96, 222.6 and 174.5 mM) and pacli-
tene derivatives and evaluated them against HCT116, MCF-7 taxel (IC50 ¼ 0.06727, 0.02581 and 0.02171 mM). Singla

ARCH PHARM
Scheme 69. Synthesis of bennzimidazole-oxindole conjugates.

ARCH PHARM
Scheme 70. Synthesis of aryl pyrazole-linked benzimidazole conjugates.
Scheme 71. Synthesis of 1-benzene acyl-2-(1-methyl indol-3-yl)-benzimidazole derivatives.

ARCH PHARM
Scheme 72. Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazole conjugates.
Scheme 73. Synthesis of cis-restricted benzimidazole derivatives.
Scheme 74. Synthesis of imidazo[2,1-b]thiazole-linked triazole conjugates.

ARCH PHARM
Table 10. SAR of microtubule inhibitors.

S. no. SAR
1
(Continued)

ARCH PHARM

S. no. SAR
4
(Continued)

ARCH PHARM

S. no. SAR
(Continued)

ARCH PHARM

S. no. SAR
10
11
12
(Continued)


S. no. SAR
13
14
et al. [127] synthesised 6-substituted-pyrazolo[3,4-d]pyrimi-

dine derivatives with 4-(1H-benzimidazol-2-yl)-phenylamine
side chain as analogues of roscovitine (Scheme 108) and
assayed at National Cancer Institute against 60 cancer cell
lines. Compound 645 was the most potent and efficacious
Scheme 75. Synthesis of beta-glucuronidase inhibitors.
derivative with GI50 (0.67–2.38 mM), TGI (1.53–6.7 mM) and
Table 11. SAR of b-glucuronidase inhibitors.

S. no. SAR
1

Scheme 76. Synthesis of novel benzofuran and related benzimidazole derivatives.
Scheme 77. Synthesis of novel thiazolo[3,2-a]benz-

imidazole derivatives.

Scheme 78. Synthesis of pyrazoline bearing benzimidazole derivatives.
LC50 (2.23–31.8 mM) values against cancer cell lines (leukae-

mia, non-small cell lung cancer, colon cancer, CNS cancer,
melanoma, ovarian cancer, renal cancer, prostate cancer and
breast cancer) using roscovitine as the reference drug
Scheme 79. Synthesis of six-2-aryl-5(6)-nitro-1H-benzimidazole (Table 12).
derivatives.
Scheme 80. Synthesis of 2-(4-chloro-3-nitrophenyl)-5-nirto-1H-benzo[d]imidazole derivatives.

ARCH PHARM
Scheme 81. Synthesis of new series of Mannich base derivatives.
Scheme 82. Synthesis of 1,3-diaryl pyrazino[1,2-a]benzimidazole derivatives.

ARCH PHARM
Scheme 83. Synthesis of novel benzimidazole derivatives containing different heterocycles.

Scheme 84. Synthesis of benzimidazole clubbed with oxadiazole ring derivatives.
Scheme 85. Synthesis of benzimidazole derivative clubbed with other heterocyclic moieties including oxadiazole nucleus.

Scheme 87. Synthesis of new benzimidazole and their N-Oxide

derivatives.
Scheme 86. Synthesis of 2-(3-(5-(4-methylpiperazin-1-yl)

methyl)-1,3,4-oxadiazol-2-yl))propyl)-1H-benzo[d]imidazole
derivatives.
Scheme 88. Synthesis of a series of Gold(I) and gold(II) complexes bearing benzimidazole and pyrazole derivatives.

ARCH PHARM
Scheme 89. Synthesis of gold(I) and gold (II) complexes.
Scheme 90. Synthesis of novel series of benzimidazole clubbed with fused rings.

ARCH PHARM
Scheme 91. Synthesis of newer benzimidazole derivatives linked to fused rings.
Scheme 92. Synthesis of novel 2-(3-methylindolyl)benzimidazole derivatives.

Scheme 93. Synthesis of new series of heterocyclic compounds bearing pyrazole nucleus linked to benzimidazole nucleus.
Scheme 94. Synthesis of heterocyclic derivatives linked to Scheme 95. Synthesis of newer 3,6-diphenylimidazo[2,1-b]
benzimidazole core. thiazole derivatives.

ARCH PHARM
Scheme 96. Synthesis of novel imidazo[2,1-b]thiazoles bearing pyrazole moieties.
Scheme 97. Synthesis of a novel series of bis-benzimidazole derivatives.
Scheme 98. Synthesis of novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives.

Scheme 99. Synthesis of novel series of hydroxyl and non hydroxyl long chain substituted 1,3,4-oxadiazole moiety bearing 2-methyl-
1H-benzimidazole derivatives.
Scheme 100. Synthesis of 2-((benzimidazole-

2-yl)thio-1-arylether-1-ones.

ARCH PHARM
Scheme 101. Synthesis of purine based benzimidazole derivatives.
Scheme 102. Synthesis of benzimidazole and benzotriazole derivatives.

ARCH PHARM
Scheme 103. Synthesis of benzimidazole-thiazolidinedione hybrids.
Scheme 104. Synthesis of (E)-benzo[d]imidazol-2 yl)methylene)indolin-2-one derivatives.

Scheme 105. Synthesis of 2,5-diamino-substituted benzimidazo[1,2-a]quinolones.
Scheme 106. Synthesis of novel triazine-benzimidazole conjugates.
Scheme 107. Synthesis of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives.

ARCH PHARM
Scheme 108. Synthesis of 6 substituted-pyrazolo[3,4-d]pyrimidine derivatives.
Table 12. SAR of miscellaneous anticancer agents.

S. no. SAR
1
(Continued)

ARCH PHARM

S. no. SAR
(Continued)

ARCH PHARM

S. no. SAR
6
(Continued)

ARCH PHARM

S. no. SAR
10
11
(Continued)

ARCH PHARM

S. no. SAR
12
13
14
(Continued)

ARCH PHARM

S. no. SAR
15
16
17
(Continued)

ARCH PHARM

S. no. SAR
18
19
20
(Continued)

ARCH PHARM

S. no. SAR
21
22
(Continued)

ARCH PHARM

S. no. SAR
23
24
25
(Continued)

ARCH PHARM

S. no. SAR
26
27
(Continued)

ARCH PHARM

S. no. SAR
28
29
30
(Continued)


S. no. SAR
31
Conclusion [8] I. Ali, S. K. Rahis-ud-din, H. Y. Aboul-Enein, A. Rather,

Cancer Ther. 2011, 8, 6–14.
Benzimidazole is a pioneer scaffold. This review highlights the [9] I. Ali, Curr. Cancer Drug Targets 2011, 11, 131–134.
status of this moiety as anticancer agent with its diverse [10] I. Ali, K. Salim, M. A. Rather, W. A. Wani, A. Haque, Curr.
biological profiles. Being commercially traced in a variety of Cancer Drug Targets 2011, 11, 135–146.
therapeutic agents, this review will help chemists to [11] I. Ali, S. K. Rahisuddin, A. Haque, A. El-Azzouny, Egypt.
synthesise newer/novel benzimidazole derivatives with their Pharmaceut. J. 2010, 9, 133–79.
vast synthetic approaches and SAR. [12] https://pubchem.ncbi.nlm.nih.gov/summary/summary.
[13] Cell Signaling Technology Inc., Safety data sheet (SDS),
The authors have declared no conflicts of interest. 2014-11-26, version: 2.
[14] L. A. Hammond, K. Davidson, R. Lawrence,
J. B. Camden, D. D. Von Hoff, S. Weitman, E. Izbicka,
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Arch. Pharm. Chem. Life Sci.

2017, 350, e1700040

Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches

Keywords: Alkylating agents / Anticancer / Benzimidazole / Topoisomerase inhibitors / Tubulin inhibitors

Introduction a mutation in normal cells [1, 2]. Glutamic acid derivatives,

ß 2017 Deutsche Pharmazeutische Gesellschaft www.archpharm.com (1 of 80) e1700040

Figure 1. Different targets of benzimidazole as

Figure 2. Benzimidazole scaffold-containing

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Table 1. Patents on benzimidazole as anticancer agents.

polymerase (PARP) inhibitor [16] which is targeted against

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Scheme 1. Synthesis of 5-substituted-4(1H-benzimidazole-2-yl)

Scheme 3. Synthesis of 1H-benzimidazole derivatives.

Scheme 2. Synthesis of benzimidazole derivatives.

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Scheme 4. Synthesis of novel benzimidazole acridine derivatives.

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Table 2. SAR of topoisomerase-I inhibitors.

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Scheme 5. Synthesis of bis(benzimidazole) derivatives.

complexes. These agents create a lesion that includes

Scheme 6. Synthesis of 2(2-hydroxyphenyl)-3H-benzo[d]imidazole-4-carboxylic acid derivative.

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Scheme 7. Synthesis of methyl 2-(2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-4-yl)-1H-benzo[d]imidazole-4-carboxylate derivative.

Table 3. SAR of topoisomerase-II inhibitors.

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Scheme 8. Synthesis of 1-methylene-2,3-diaryl-1,2-dihydro pyrazino[1,2-a]benzimidazole derivatives.

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Scheme 9. Synthesis of 1-(2-aryl vinyl)-3-aryl pyrazino[1,2-a]benzimidazole derivatives.

Scheme 11. Synthesis of 2-pyridyl benzimidazole, oxazole and

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Scheme 12. Synthesis of bis-benzimidazoles having 2-aryl moieties.

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Scheme 13. Synthesis of N-(3-(dimethyl amino)propyl)-4-(5-methyl-3H-indole-2-yl)benzenamine derivatives.

Scheme 14. Synthesis of 4-(6-methyl-1H-benzo[d]imidazole-2- Scheme 15. Synthesis of bis-(4-[3-chloropropanamide]phenyl)-

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Scheme 16. Synthesis of C-8 linked PBD-benzimidazole conjugates.

Scheme 17. Synthesis of novel PBD-benz-

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Scheme 18. Synthesis of benzimidazole-4,7-diones.

(Schemes 47–49). Compound 226 was found to be more

Scheme 20. Synthesis of 2-(chloromethyl)-1-

Scheme 21. Synthesis of 2-(bromomethyl)-1-methyl-4,5,dichloro-1H-imidazole cyclohexa-2,5-diene-1,4-dione.

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Scheme 22. Synthesis of 1,5,6-trimethyl-2-(2-nitropropan-2-yl)-1H-benzo[d]imidazole-4,7-dione derivatives.

Scheme 23. Synthesis of 1,5,6-trimethyl-2-(2-meth-

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Scheme 25. Synthesis of novel 1-(4 methoxyphenethyl)-1H-1benzimidazole-5-carboxylic acid derivatives.

Microtubule inhibitors Taher et al. [79] reported synthesis of some conjugates by

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Scheme 27. Synthesis of copper complexes

Scheme 28. Synthesis of platinum complexes containing benzimidazole derivatives.

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Table 4. SAR of DNA intercalation and alkylating agents.

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Scheme 29. Synthesis of 5,6-dichloro-benzimidazole derivative.

Scheme 30. Synthesis of 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-1-(ethylthio)propan-2-ol.

Scheme 31. Synthesis of novel 2-(2,2,2)-triﬂuoroethyl-benzimidazole scaffold.

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Scheme 32. Synthesis of 2-(5,6-dichloro-1H-benzimidazole[d]imidazol-2-yl)-1,1,1-triﬂuoro-4-(2,2,2-triﬂuoroethylthio)butan-2-ol

Scheme 33. Synthesis of 2-aryl benzimidazole-4-carboxamide derivatives.