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Benzimidazole scaffolds as promising antiproliferative agents: a review
BMC Chemistryvolume 13, Article number: 66 (2019)
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.
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 . 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 .
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 . 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 . 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 , anticancer , antimicrobial , antihistamine , antihelmintic , antioxidant , antihypertensive , antiviral , anticoagulant  and antiulcer activity . 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 . 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 .
Benzimidazole derivatives as antiproliferative agents
Abonia et al. synthesized new derivatives of 1,2,5-trisubstituted benzimidazole and screened for their antiproliferative activity against the 60 human cancer cell lines (leukemia, melanoma, lung, colon, brain, ovary, breast and kidney carcinoma etc.) using SRB protein assay to estimate cell growth. Among the synthesized compounds, compounds 1a and 1b (Fig. 2) displayed the utmost potency towards lung, melanoma and leukemia cancer cell lines (GI50 values 1.15–7.33 µM and 0.167–7.59 µM), respectively and LC50 values more than 100 µM .
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, Fig. 2) .
Coban et al. synthesized a new series of 1H-benzimidazole compounds and screened for its cytostatic studies using HeLa, MCF7 and A431 cancer cell lines by MTT assay. Compound 3a exhibited the most profound cytotoxicity and comparable to standard drug (Table 3, Fig. 2) .
Demirayak et al. reported a series of pyrazino[1,2-a]benzimidazole derivatives and evaluated for its in vitro anticancer activity against 60 human malignant cell lines: leukaemia (L), melanoma (M), NSCLC, CC, CNSC, OC, RC, PC and BC by SRB protein assay. Among the synthesized compounds, compound 4a was found to be most active anticancer agent and comparable to standard drugs (Table 4, Fig. 2) .
Dettmann et al. developed a new series of 2-phenyl-1-[4-(2-piperidin-1-yl-ethoxy) 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) .
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 (Table 5, Fig. 2) .
Gao et al. synthesized a novel series of benzimidazole acridine derivatives and evaluated for its in vitro cytotoxicity toward human erythroleukaemia K562 and malignant hepatoma HepG-2 cells by MTT assay. From this series, compound 7a exhibited maximum cytotoxicity against both K562 (IC50 = 2.68 µM) and HepG-2 (IC50 = 8.11 µM) cells as compared to standard drugs colchicin (IC50 = 1.80 µM for HepG-2) and imatinib (IC50 = 0.47 µM for K562) (Table 6, Fig. 2) .
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 (IC50 ± 3 µM) and comparable to mitomycin C with IC50 ± 0.9 µM (Fig. 2) .
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 IC50 = 3 µM (Fig. 2) .
Guan et al. developed a new class of benzimidazole carbamates with indole moiety and accessed for its antiproliferative activity against three tumor cell lines (SGC-7901, A-549 and HT-1080) using MTT assay. In this series, compound 10a displayed the highest antiproliferative activity towards selected cancer cell lines (Table 7, Fig. 2) .
Hranjec et al. synthesized new benzimidazole substituted Schiff bases and evaluated for their in vitro antiproliferative activity toward human cancer cell lines i.e. HeLa (cervical carcinoma), SW620 (colorectal adenocarcinoma, metastatic), MiaPaCa-2 (pancreatic carcinoma), MCF-7 (breast epithelial adenocarcinoma, metastatic) and WI38 (normal diploid human fibroblasts) by MTT assay. From the synthesized compounds, compounds 11a and 11b displayed highest antiproliferative activity (Table 8, Fig. 2) .
Hranjec et al. synthesized a new series of novel benzimidazole derivatives and evaluated for its antiproliferative activity on five different cancer cell lines: HeLa, pancreatic (MiaPaCa-2), colon (SW 620), MCF-7 and lung (H 460) cell lines by MTT assay. Among them, compounds 12a and 12b displayed the highest activity on tested cell lines and demonstrated an exceptional selectivity for HeLa cells (Table 9, Fig. 2) .
Husain et al. synthesized a new class of benzimidazole having oxadiazole and triazolo-thiadiazoles moiety and evaluated for its in vitro anticancer potential at concentration (10 µM) against NCI 60 cell lines by five dose assay. Compound 13a displayed considerable growth reticence with GI50 efficacy from 0.49 to 48.0 µM especially in lung carcinoma cell HOP-92 (GI50 0.49, TGI 19.9, LC50 > 100 and Log10GI50 − 6.30, Log10TGI − 4.70, Log10LC50 > − 4.00) (Fig. 2) .
Husain et al. synthesized benzimidazole derivatives associated with triazolo-thiadiazole and triazolo-thiadiazine nucleus and screened for their in vitro anticancer potential at only concentration (10−5 M) toward NCI 60 cell lines by five dose assay. Among the synthesized compounds, compound 14a (Fig. 2) exhibited excellent results against 60 cell panel (MG-MID − 6.07, − 5.51 and − 4.85 value of log10 GI50, log10 TGI and log10 LC50, respectively) .
Kamal et al. synthesized novel terphenyl benzimidazole derivatives and screened for their antitumor potency in tumor cells i.e. oral, lung, ovarian, cervix, colon, breast and prostate cells by SRB method. Among the synthesized compounds, compounds 15a and 15b showed significant anticancer potency with GI50 values vary from < 0.1 to 2.11 µM, whereas the positive control reference adriamycin demonstrated the GI50 value from 0.1 to 7.25 µM (Fig. 3) .
Kamal et al. synthesized novel 2-aryl 1,2,4-oxadiazolo-benzimidazole compounds and evaluated for their in vitro anticancer screening against 60 tumor cell lines by SRB method. In this series, compounds 16a and 16b displayed significant cytoxicity against the majority of tumor cells with GI50 range from 0.79 to 28.2 µM (Fig. 3) .
Lukevics et al. developed novel trimethylsilylpropyl substituted benzimidazole derivatives and screened for their anticancer activity on mouse hepatoma (MG-22A), human fibrosarcoma (HT-1080), mouse melanoma (B16), mouse neuroblastoma (Neuro 2A) and normal mouse fibroblast cells by MTT assay. In this series, compounds, 17a and 17b showed significant activity in mouse melanoma (B16) having TD50 from 0.001 to 0.008 µg/mL. In vivo screening of compound 17a showed high anticancer activity toward sarcoma S-180 by 62% (Fig. 3) .
El-Nassan, synthesized a new series of benzimidazole derivatives and demonstrated for its in vitro anticancer activity on MCF7 by SRB assay. Among the synthesized derivatives, compound 18a (IC50 = 0.0390 µM) exhibited promising antitumor activity (Fig. 3) .
Paul et al. synthesized novel coumarin–benzimidazole conjugates and tested for their in vitro anticancer potency on 60 cancer cell lines by SRB assay. In this series, compound 19a was found to be most active agent against leukemia, breast, colon, prostate (PC-3) and melanoma (LOX IMVI) cancer cell lines, respectively and comparable to the standard drug (5-FU) (Table 10, Fig. 3) .
Paul et al. designed and synthesized novel quinazoline and benzimidazole conjugates and evaluated in vitro for their antitumor activity on 60 human tumor cell lines at a dose of 10 µM. From this series, compounds 20a, 20b and 20c were found to be most active against selected cancer cell lines (Table 11, Fig. 3) .
Ramla et al. synthesized a novel series of benzimidazole derivatives and evaluated for its inhibitory activity against Burkitt’s lymphoma by Epstein–Barr virus activation test. In this series, compound 21a exhibited 12.3% inhibitory activity (Fig. 3) .
Ranganatha et al. synthesized new benzophenone–benzimidazole derivatives and evaluated for their in vivo tumor inhibition against EAC cells via three independent assays (trypan blue dye exclusion, MTT and LDH release assay) using DMSO as a vehicle control. Compounds, 22a and 22b exhibited the highest cytotoxic effect (IC50 ~ 10 μM and ~ 16 μM) among the synthesized derivatives (Fig. 3) .
Rashid et al. synthesized benzimidazoles with oxadiazole nucleus and evaluated for their in vitro anticancer activity at a single dose (10 µM) in NCI 60 cell line panel using SRB assay. In this series, compound 23a with GI50 values between 0.79 and 17.8 µM showed significant anticancer activity against tested cell lines (Fig. 3) .
Reddy et al. synthesized novel pyrazole containing benzimidazole conjugates and screened for their anticancer activity (growth inhibition) against lung-A549, MCF-7, HeLa and human keratinocyte cells-HaCaT using MTT assay. Among the synthesized derivatives, compounds 24a, 24b and 24c exhibited effective anti-proliferative activity toward cancer tested cell lines (Table 12, Fig. 4) .
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) .
Rewcastle et al. synthesized a series of benzimidazole analogs and evaluated for its enzyme activity against the p110α, β and δ isoforms of PI3K using a lipid kinase assay and also assessed for their antitumor activity against two human cancer cells lines, NZOV9 (Y1021C mutation of p110α enzyme) and NZB5 (wild-type p110α enzyme) using cell proliferation assay. From this series, compound 26a exhibited best enzyme potency and also inhibiting tumor growth by 56.3 ± 2.6% (Table 14, Fig. 4) .
Rodionov et al. synthesized novel ferrocenylalkyl 2-mercaptobenzimidazole derivatives and screened for their in vivo antitumor activity against the murine solid tumor, carcinoma 755 (Ca755), transplanted in mice. Among the synthesized compounds, compound 27a showed 87% tumor growth inhibition on carcinoma 755 at the dose of 250.0 mg/kg day as compared to control cisplatin (Fig. 4) .
Salahuddin et al. synthesized a novel series of benzimidazole molecules and screened for its in vitro anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines. From this series, compound 28a displayed promising activity against MDA-MB-468 (breast cancer) and SK-MEL-28 (melanoma) (GP = 36.23 and 47.56, respectively) (Fig. 4) .
Sharma et al. synthesized new benzimidazole–quinazoline conjugates and monitor for their growth inhibitory activity on 60 tumor cell lines. Among them, compound 29a exhibited superior activity on leukemia, colon and melanoma cancer cell lines as compared to standard 5-fluorouracil (Table 15, Fig. 4) .
Sharma et al. synthesized novel purine-benzimidazole conjugates then screened for their anticancer activity against 60 human malignant cell lines by Aurora-A kinase assay. Among them, compound 30a exhibited 1.25 fold more activity with GI50 value of 18.12 µM (MG-MID) than the reference 5-FU, GI50 = 22.60 µM (Fig. 4) .
Yoon et al. synthesized a new class of benzimidazole derivatives and evaluated in vitro for its antiproliferative activity using human breast cancer MCF-7 and MDA-MB-468 cells by inner salt assay. From this series, compounds 31a, 31b and 31c showed good antiproliferative activity against MCF-7 and MDA-MB-468 cells (Table 16, Fig. 4) .
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) .
Wang et al. synthesized new chain of benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives and screened for its tubulin polymerization inhibitory activity and cytotoxicity against anthropic A549, HepG2 and MCF-7 tumor cell lines by MTT assay. Among the synthesized derivatives, compound 33a displayed excellent activity and comparable to colchicine and CA-4 as standards (Table 18, Fig. 5) .
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, Fig. 5) .
Madabhushi et al. synthesized some new benzimidazole functionalized chiral thioureas and screened for their cytotoxic activity against the human cancer cell lines (A549, MCF7, DU145 and HeLa) by MTT assay. From the synthesized compounds, compound 35a found to display significant activity against A549, DU145 and HeLa cell lines (Table 20, Fig. 5) .
Yadav et al. designed and synthesized a series of new benzimidazole derivatives and accessed for its cytotoxic potential against MCF7 (human breast adenocarcinoma cancer) cell line by SRB technique and compared to 5-FU and carboplatin standard drugs. In this series, compound 36a displayed the most potent anticancer activity (Table 21, Fig. 5) .
Yadav et al. synthesized some 2-(1-benzoyl-1H-benzo[d]imidazol-2-ylthio)-N-substituted acetamide derivatives and evaluated for their anticancer activity against MCF7 and HCT116 cancer cell lines by SRB assay using tamoxifen and 5-FU as references. Among the synthesized compounds, compounds 37a and 37b emerged out as excellent anticancer agents (Table 22, Fig. 5) .
Yadav et al. synthesized a class of novel benzimidazole derivatives and screened for its antitumor potency towards HCT116 cancer cell line by SRB method and comparable to standard drug 5-FU. Compound 38a showed prominent antitumor activity (Table 23, Fig. 5) .
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) .
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) .
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) .
Aikman et al. developed some gold(III) pyridine-benzimidazole complexes and evaluated for their antitumor activity against human SKOV-3, A375, MCF-7 and A549 cancer cell lines by MTT assay using Auphen (stock solution 10 mM in DMSO) as reference. Compounds 42a–42c showed promising anticancer activity, particularly in the melanoma A375 cancer cell line (Table 27, Fig. 6) .
Onnis et al. synthesized a series of novel benzimidazolehydrazones and evaluated for its anticancer activity against murine leukemia (L1210), T-lymphoblastic leukemia (CEM), cervix carcinoma (HeLa) and pancreas carcinoma (Mia Paca-2) cell lines. In this series, compounds 43a and 43b inhibited the growth of all tested cell lines (Table 28, Fig. 6) .
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 (Table 29, Fig. 6) .
Tahlan et al. designed and synthesized some novel benzimidazole derivatives and accessed for their antiproliferative potential towards HCT116 cancer cell line by SRB method. Among the synthesized derivatives, compound 45a displayed the most potent anticancer activity (Table 30, Fig. 6) .
Wang et al. developed a class of novel substituted benzimidazole derivatives and evaluated its antiproliferative activity against MGC-803, MCF-7, HepG2 and MFC cells by MTT colorimetric assay. In this class, compound 46a showed remarkable anticancer activity as compared with standard drugs 5-FU and chrysin (Table 31, Fig. 6) .
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) .
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 cancer cell lines such as HCT116, MCF7, HepG2, HeLa, A549 and A431. Benzimidazole has established huge alertness in current time and is extremely significant heterocyclic pharmacophore in recent drug innovation and medicinal chemistry.
Availability of data and materials
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
Ehrlich Ascites Carcinoma
non-small-cell lung carcinoma
central nervous system cancer
breast adenocarcinoma 7
human colorectal carcinoma
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The authors are thankful to Head, Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, for providing necessary facilities to carry out this research work.
The authors declare that they have no competing interests.
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