Benzimidazole scaffolds as promising antiproliferative agents: a review

Cancer is one of the most serious medical problem and second leading cause of death in the world, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth. The benzimidazole is a heterocyclic moiety found in extensive number of natural and biological active molecules. Benzimidazole derivatives might be considered as auxiliary isosters of nucleotides having attached heterocyclic cores in their structures, cooperate effortlessly with biopolymers and have potential action for chemotherapeutic applications. Benzimidazole and its derivatives displayed a wide range of biological activity because of its structural similarity with the naturally occurring nucleotides. Benzimidazole has established huge alertness in current time and is extremely significant heterocyclic pharmacophore in recent drug innovation and medicinal chemistry. The present review summarizes the chemistry of various substituted benzimidazole derivatives with their antiproliferative significance towards the various cancer cell lines such as HCT116, MCF7, HeLa, HepG2, A549 and A431.


Introduction
Cancer is one of the most serious medical problem and second leading cause of death in the world, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth. Hence there is a need to develop those agents whose chemical characteristics clearly differ from those existing agents and can overcome the problem of resistance. In present situation, the most engaged and demanding undertaking is the design, synthesis and development of new biologically active heterocycle compounds. Heterocyclic entities act as medications since they have precise synthetic reactivity and they give advantageous site to which bioactive substituents can be bind. Subsequently, there is need for the improvement of pharmacologically active heterocycles in synthetic and therapeutic science with certain focal points including its effortlessness of activity, greener methodology, simple workup strategy, selectivity, higher yields and high-particle monetary [1,2].
In the medicinal field, the utility of heterocyclic entities has been raising each day because of structural similarities with biological molecules like nutrients, antibiotics. In spite of the fact that it including almost one-fourth of best hundred offering drugs yet because of issues like obstruction, poisonous quality, there is a requirement for minor change in existing drug molecules and to structure novel molecules which fuse benzimidazole as pharmacophore which are active against new targets [3]. Substituted benzimidazole might be a vital pharmacophore in bioactive agent innovation. Recently, noticeably consideration has been given to the design and synthesis of substituted benzimidazoles. Current perceptions advocate that substituted benzimidazoles and heterocycles demonstrate interface with the biopolymers, have potential action with lower toxicities. The substituted benzimidazoles are helpful for the improvement of ongoing scaffolds of pharmaceutical or natural concern [4].
Benzimidazole is also named as 3-azaindole, azindole, benziminazole, benzoglyoxaline, 3-benzodiazole, 1,3-diazaindene having melting point of 170-172 °C and occurs as white crystals [5]. Benzimidazole is an important structural motif found in extensive number of natural and pharmacologically active molecules. Especially, the benzimidazoles might be considered as auxiliary isosters of nucleotides having attached heterocyclic cores in their structures, cooperate effortlessly with biopolymers and have potential action for chemotherapeutic applications [6]. The benzimidazole moiety itself is an urgent pharmacophore in present day and has been used as privileged scaffolds to synthesize selective drugs of interest in numerous therapeutic areas including HIV-RT inhibitor [7], anticancer [8], antimicrobial [9], antihistamine [10], antihelmintic [11], antioxidant [12], antihypertensive [13], antiviral [14], anticoagulant [15] and antiulcer activity [16]. The marketed drugs having benzimidazole moiety ( Fig. 1) i.e. (i) nocodazole, (ii) bendamustine, (iii) veliparib, (iv) glasdegib, (v) crenolanib, (vi) abemaciclib, (vii) liarozole, (viii) pracinostat. Malignancy is a gathering of various dangerous ailments described by uncontrolled development of cells, prompting attack of encompassing tissue and regularly spreading to different parts of the body [17]. Development of resistance and toxicity to normal rapidly growing cells are the major limitations of existing anticancer drugs, also majority of the drugs in the market that are not specific [8].
Azam et al. developed a new series of 2-substituted benzimidazoles and screened for its cytotoxicity against selected human tumor cell lines: leukemia (THP-1), MCF-7, PC-3 and adenocarcinomic alveolar basal epithelial cell line (A-549) by trypan blue exclusion method. Among the synthesized compound, 2a exhibited promising activity against the tested cancer cell lines (Tables 1 and 2 benzyl]-1H-benzimidazole derivatives and evaluated for its cytotoxicity against human MCF-7 and MDA-MB-231 breast cancer cell lines. Among the synthesized derivatives, compound 5a displayed highest cytostatic effects (T/Ccorr ≈ 0%) and comparable to reference (T/Ccorr = 0-20%) effects at a concentration of 5 µM than the standard drug cisplatin (Fig. 2) [21].
Galal et al. synthesized a new class of benzimidazole-5-carboxylic acid derivatives and evaluated for its anticancer activity (growth inhibitory) against 21 human tumor cell lines (seven colon, eight lung and six gastric) by SRB assay. Compounds 6a and 6b showed 10 times superior inhibitory result than etoposide as reference ( Gellis et al. synthesized novel benzimidazole-4,7-dione molecules and evaluated for their cytotoxicity on colorectal, breast and lung cancer cell lines using MTT assay. Among the synthesized compounds, compound 8a showed tremendous activity (IC 50 ± 3 µM) and comparable to mitomycin C with IC 50 ± 0.9 µM (Fig. 2) [24].
Gowda et al. reported a new series of benzimidazole-5-carboxylic acid derivatives and evaluated for its anticancer activity on K562 and CEM cancer cell using DMSO as vehicle control by the trypan blue and MTT assays. In this series, compound 9a exhibited maximum apoptosis in leukemic cell accompanying an IC 50 = 3 µM (Fig. 2) [25].
Refaat et al. synthesized a novel series of 2-substituted benzimidazole derivatives and evaluated in vitro for its anticancer potency against HEPG2, MCF7 and HCT116 cell lines by SRB assay using doxorubicin as reference. Among the synthesized compounds, compounds 25a and 25b showed the highest potency against HEPG2 while compounds, 25c, 25d and 25e showed promising activity against MCF7. Compounds, 25d and 25e showed moderate activity against HCT116 (Table 13, Fig. 4) [40].
Yang et al. synthesized new symmetrical bis-benzimidazoles derivatives and evaluated in vitro for their cytotoxicity on HeLa, SKOV-3 and BGC-823 cell lines by MTT assay. In this series, compounds 32a, 32b and 32c displayed significant activity against tested cancer cell lines (Table 17, Fig. 5) [47].
Wang et al. reported novel benzimidazole-2-urea derivatives and tested for their antiproliferative activity against a group of human tumor cells using MTT assay. In this series, compound 34a exhibited the potent antiproliferative activity and compared to standard drugs (Table 19,     Tahlan et al. synthesized a series of new 2-mercaptobenzimidazole Schiff base derivatives and evaluated for its antitumor potency against HCT116 cancer cell line by SRB method using 5-FU as reference. In this series, compounds 39a and 39b showed significant antitumor activity towards tested cell line (Table 24 and Fig. 5) [8].
Tahlan et al. reported a class of novel benzimidazole azomethine derivatives and screened for its anticancer potency against HCT116 cancer cell line by SRB method using 5-FU as standard. Among the synthesized compounds, compound 40a was found to be most potent anticancer agent against selected cancer cell line (Table 25 and Fig. 5) [9].
Mohammed et al. synthesized a class of new substituted benzimidazoles and screened for its anticancer activity against breast adenocarcinoma MCF-7, lung carcinoma A549 and epithelioid cervix carcinoma HeLa using SRB colorimetric assay. Among the synthesized compounds, compounds 41a and 41b were found to be most active anticancer agents and comparable to the cisplatin (reference drug) ( Table 26, Fig. 6) [54].
Tahlan et al. designed and synthesized a series of substituted benzimidazole benzamide derivatives and screened for its anticancer potency against HCT116 cancer cell line by SRB method using 5-FU as standard. In this series, compound 44a and 44b were found to be most potent compounds against tested cell line (     showed remarkable anticancer activity as compared with standard drugs 5-FU and chrysin (Table 31, Fig. 6) [59]. El-Gohary et al. designed and synthesized a class of novel benzimidzole scaffolds and screened for its in vitro antiproliferative activity against three different cancer cell lines i.e. HepG2, HCT-116, MCF-7 and normal (W138) cell lines employing MTT assay. Among the synthesized compounds, compound 47a displayed significant antitumor activity and comparable to standard 5-FU (Table 32, Fig. 6) [60].

Conclusion
Benzimidazole is a promising category of bioactive heterocyclic compound that exhibit wide variety of biological activities because of its structural similarity with the naturally occurring nucleotides and also a focusable moiety in discovery of novel drug design in medicinal field. The present review summarizes the chemistry of various substituted benzimidazole derivatives with their antiproliferative significance towards the various