INTRODUCTION:

As per the World Health Organization (WHO) data - 2019, cancer is a major public health and economic issue and is a leading cause of death worldwide¹. In 2020, Global cancer incidence was 19.3 million. Breast cancer was one of the major cancer with 2.3 million new cases, accounting for 11.7% of all cancer cases. Breast cancer holds fifth position in the list of leading causes of cancer-related deaths worldwide². There are two major categories of Breast cancer cells: estrogen receptor positive (ER+) and estrogen receptor negative (ER), depending on their evolution from different cell lineages. The ER antagonists have limited clinical utility for the treatment of ER+ breast cancer because of side effects, whereas ER breast cancer, especially the triple-negative subtype, has no efficient treatments till now due to the lack of specific targets.

Therefore, endocrine therapy is not effective in the treatment of ER breast cancer patients and therefore such patients face a lot of problems such as poor prognosis, greater rate of distant metastases, and a high death rate³.

Surgery and radiotherapy are effective strategy for the treatment of early stage breast cancer while chemotherapy, hormonal and targeted therapies are employed in the treatment of aggressive stage. Tamoxifen and anastrozole are the common drugs to treat Hormone sensitive tumours while in case of HER-2 (human epidermal growth factor receptor) positive tumours, herceptin is used. 70% of patients report failure to respond to treatment with HER2-positive cancer, while in case of treatment with Tamoxifen and anastrozole a high incidence of resistance is noted. Triple negative breast cancers (TN) where tumours lacking the estrogen (ER), progesterone (PR), and HER2 receptors, are highly heterogenous and a significant therapeutic challenge⁴.

The heterocyclic benzimidazole nucleus (Fig: 1) is very important and widely used pharmacophore for the development of new drug molecules in the field of synthetic medicinal chemistry. It can also be obtained from naturally occurring compounds such as cyanocobalamin. The structural similarity of benzimidazole nucleus to the naturally occurring nucleotides empowers it to target the polymers in the living world leading to its great significance in the biological systems⁵. Benzimidazole derivatives have been frequently used as medicine in human and animals since the 1960s because of their minimal cost, superior efficacy, and safety without any serious adverse effects. This review covers the anticancer effect and the mechanisms of benzimidazole derivatives against breast cancer².

Fig: 1: Benzimidazole nucleus

Anticancer Action of Benzimidazole:

Benzimidazole based compounds have got much attention because of their significant cytotoxic potential. A number of benzimidazole based anticancer drugs have received US FDA approval in the last one decade. Recently, Binimetinib, Selumetinib and Abemaciclib has been approved for the treatment of various mutated types of cancer⁶. Benzimidazole produced their anticancer activity through versatile mechanisms of action including alkylation of DNA, DNA binding, interrupting tubulin polymerization or depolymerization, antiangiogenic, signal transduction inhibitors and enzyme inhibition⁷ (Fig 2). Examples of some marketed benzimidazole derived anticancer agents are as follows:

Fig: 2: Anticancer mechanism of benzimidazole

Benzimidazole Derivatives as Anti-Breast Cancer Agents:

Various researchers have reported significant anti-breast cancer activities of wide range of benimidazole derivatives time to time that may serve as a basis for consideration of benzimidazole as promising scaffold for the development of potential anti-breast cancer drugs.

Anichina K et al (2021) synthesized a series of benzimidazolyl-2-hydrazones as potential microtubule-targeting agents. In vitro cell proliferation assay on breast cancer cell line MCF-7 as well as normal cell line 3T3 revealed that the synthesized benzimidazole derivatives show promising effect against breast cancer with IC50 values in the range of 17.40–95.4 μg/mL and 16.7–24.7 respectively⁸.

Chojnacki K et al (2021) synthesized efficient protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole and tetrabromo-benzotriazole. Cellular assays on two various breast cancer cell lines rendered promising results for 4-(4,5,6,7-tetrabromo-2-methyl-1Hbenzimidazol-1-yl)propyl hexanoate⁹.

Choi HS et al (2021) evaluated the anticancer effect of well-established anthelmintic benzimidazole derivatives called mebendazole (MBZ) on triple-negative breast cancer (TNBC) and investigated its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDAMB-231, and allograft mice were treated with mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. Liver and kidney toxicity, body weight changes, tumour volume, and incidence of lung metastasis were also analysed in mice. MBZ significantly induced DNA damage, cell cycle arrest, down regulation of cancer stem cell markers CD44, OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. MBZ could be an efficaceous anticancer agent that can be used to overcome treatment resistance in TNBC².

Karaaslan C et al (2018) synthesized some new benzimidazole carboxamidines and screened for their antiproliferative activity against human breast cancer cell line MCF-7. All tested compounds showed prominent growth inhibitory effect. The IC50 results of many compounds are even more active than the reference compounds used in the clinic and have been promising in developing new anticancer drug¹⁰.

Al-Douh MH et al find some benzimidazole derivatives with high cytotoxic activity against MCF-7 cell lines with IC50 = 8.86±1.10 μg/mL, and moderate cytotoxic activity against HCT-116 cell lines with IC50=24.08±0.31 μg/mL, and determined these benzimidazoles derivatives are suitable candidates for the development of new anti-cancer drugs¹¹.

Błaszczak-Świątkiewicz K et al determined cytotoxic activity of some N-oxide benzimidazoles derivatives against breast cancer cell lines and revealed that nitro derivatives of N-oxide benzimidazole have greater cytotoxic potential. N-oxide binding and nitro-substituence may potentially affect benzimidazole selectivity and affinity to tumor cells, especially in hypoxic conditions¹².

Chojnacki K et al synthesized a series of new aminoalkyl-,5,6,7-tetrabromo-1Hbenzimidazole (TBBi) and 4,5,6,7-tetrabromo-1Hbenzimidazole (TBBt) derivatives. Evaluation of anti-proliferative activities against CCRF-CEM, MCF-7 and PC-3 human cancer cell lines provided interesting results. New alkylaminederivatives of TBBi and TBBt reduce the viability of cancer cells much more strongly than their parent compounds. Some of the compounds inhibited the viability of tumor cells even more effectively than the known and approved for clinical trials compound CX-4945¹³.

Zhang J et al designed and synthesized some benzene sulphonamide derivatives of benzimisazole. The kinase inhibition assay of these compounds revealed that some compounds potently inhibits G9a with an IC50 of 1.32 μM and the MTT assay showd that MCF-7 is highly sensitive to these compounds among five different breast cancer cells¹⁴.

Mostafa AS et al designed and synthesized three series of 2-phenyl benzimidazole-based compounds and determined the cytotoxic activities against MCF-7 cell lines. One of the compound exhibited even more potency than the standard drug doxorubicin with IC50 value of 3.37 µM. Some of the compounds showed good cytotoxic activities with IC50 values of 5.84 and 6.30 µM, respectively. The rest of compounds exhibited moderate to low activity¹⁵.

Srour AM et al designed and synthesized a new class of thiazol-benzimidazole compounds as EGFR PK inhibitors targeting human breast cancer (MCF-7). All the newly synthesized compunds were evaluated for their potential suppression activity against EGFR. Few compounds revealed more potent inhibiting effect than erlotinib, displaying IC50 values ranging from 71.67 to 150.36 nM vs IC50 erlotinib, 152.59 nM. On the other hand, some compounds showed 1.3–1.8 folds reduction in the potency in comparison with erlotinib revealing IC50 values; 208, 212, 278 nM¹⁶.

Liang Y et al synthesized four benzimidazole-containing selenadiazole derivatives (BSeDs). The BSeDs synthesized in this study exhibited potential anticancer activities against the two classic breast cancer cell lines, MCF-7 and MDA-MB-231. These compounds were found to show greater cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 than MCF-7 cells. The results demonstrated that BSeDs can induce cell-cycle arrest and apoptosis in MDA-MB-231 cells by inducing DNA damage, inactivating AKT and activating MAPK family members through ROS overproduction¹⁷.

Galal SA et al designed and synthesized some pyrimidine-benzimidazole conjugates and investigated their activity against Chk2, alone and in combination with the cisplatin and doxorubicin on breast carcinoma, (ERþ) cell line (MCF-7). The results indicated that conjugated compounds exhibited potent inhibition effect against enzymatic activity of Chk2. These compounds also potentiated the activity of both cisplatin and doxorubicin. The foregoing results necessitated further elucidation of pyrimidine-benzimidazole conjugates¹⁸.

Rasal NK et al synthesized hybrid analosgs of 2, 4-dimethyl-1Hpyrrole and benzimidazole moieties via molecular hybridization and screened against the full NCI 60-cell line panel. As per the results obtained from in vitro anticancer evaluation, compound one of the compound (NSC 188468) recognized as a most potent compound with the highest growth inhibition against MDA-MB-435 cell line of melanoma (62.46%) and MDA-MB-468 cell line of breast (40.24%). This compound also illustrated suitable pharmacokinetic properties. Overall, in vitro anticancer evaluation together with in silico studies, revealed that this could be considered as structural permutations to discover the more potent anticancer agent¹⁹.

Dhanwal V et al synthesized and investigated the anticancer activity of 1,2-disubstituted benzimidazole derivative and its organic nanoparticle (BZ6-ONPs) in various cancer and normal cell lines. BZ-ONPs showed its enhanced cytotoxic potential (~5 fold) compared to the BZ alone in MCF-7 cells, which reasonably attributed to its increased uptake into the tumor cells/spheroids. Further, the BZ-ONPs induce oxidative stress-mediated ROS activity leading to mitochondrial damage and loss of cell proliferation in human breast cancer cells. Its hassle free preparation, suitable photo-physical properties and strong anticancer activities proclaim this formulation (nanoparticles) as promising anti-cancer agent²⁰.

Nashaat S et al synthesized a new series of benzimidazoles core compounds with dithiocarbamate and thiopropyl link conjugated with different secondary amines and evaluated for their anti-breast cancer activity using MCF7 cell line. Pin 1 enzyme was chosen as a new goal for breast cancer targeting. Results revealed that many of the synthesized compounds were the most potent anti-breast cancer. Molecular modeling study was conducted to understand the compounds binding to Pin 1, docking study proved a similar binding mode of these compounds to reference co-crystallized ligand to Pin 1 enzyme. Contact statistics and surface map studies stated the similarity between active candidates, which assures their fitting to active site of Pin 1 enzyme²¹.

Thimmegowda NR et al synthesized trisubstituted benzimidazole and found that one of the compound significantly inhibited MDA-MB231 human breast cancer cell proliferation, which may be due to presence of electron withdrawing groups at para position and electron donating groups at meta position in amide. Further, synthesis of novel benzimidazole derivatives by changing the substituents at first, second and fifth position of the benzimidazole nucleus to enhance the anticancer activity is under progress at their laboratory²².

Shi DF et al synthesized a new series of 2-(4-aminophenyl) benzothiazoles and they found that molecules are chemically robust and display potent inhibitory properties in a range of cell types in vitro. The effectiveness of one of the compound, 2-(4-amino-3-methylphenyl) benzothiazole, extends to useful inhibition of a panel of human breast cancer models in nude mice. Although pharmacological mechanism is not clear yet, the possibility that the compounds might act by a novel mechanism makes the search for a pharmaceutically suitable candidate for clinical trial an urgent one²³.

Azami Movahed M et al designed and synthesized a series of pyrazino [1,2-a]- benzimidazoles which could show COX-2 inhibitory activity. The majority of synthesized compounds were selective inhibitors of COX-2 isozyme. Anti-platelet aggregation and anti-proliferative activity against MCF-7 cell line were also investigated which demonstrated acceptable activities²⁴.

Zhen Y et al reported, that flubendazole, a benzimidazole comound with well-established anthelmintic activity, induces autophagic cell death and regulates autophagy and apoptosis by targeting EVA1A, which has an anti-proliferation and anti-migration value in triple negative breast cancer (TNBC). These results provide novel perception into exploring the anti-cancer efficacy of flubendazole, implying that this commonly used anthelmintic drug may be repurposed as a novel anticancer agent. This study assumed the use of this new autophagy inducer in future TNBC therapeutics²⁵.

Zuo D et al synthesized a novel compound Methyl 5-[(1H-indol-3-yl) selanyl]-1H-benzoimidazol-2-ylcarbamate (M-24) an analogue of nocodazole that exhibited potent anticancer properties against HeLa and MCF-7 cells through disrupting microtubule polymerization and inducing G2/M phase arrest, and then causing cell apoptosis. Therefore, M-24 is a promising microtubule targeting agent that has great potentials for therapeutic treatment of human cervical and breast cancers²⁶.

Abdul Rahim AS et al synthesized a new series of N-sec/tert-butyl substituted benzimidazole derivatives. The results of the antiproliferative studies showed that these N-sec/tert-butyl-2-arylbenzimidazoles unexpectedly exhibited antiproliferative activity selective towards MDA-MB-231 breast cancer cell lines. The unsubstituted sec-butyl-2-phenylbenzimidazole with IC50 of 29.7 µM was the most potent candidate of this series against MDA-MB-231 cancer cell line. Therefore, this compound may serves as template for future studies to discover new chemotherapeutic agents with enhanced selectivity towards ER breast cancer²⁷.

Inhibition of aromatase has been an effective approach for hormone-dependent breast cancer therapy in the postmenopausal women. Imidazole and triazole nucleus are important heterocyclic rings for the development novel efficaceous aromatase inhibitors with greater affinity for the enzyme. Acar Çevik U et al synthesized a series of benzimidazole-triazolothiadiazine derivatives with different substituents at benzimidazole and phenyl rings. The newly synthesized compounds were evaluated for their anti-cancer properties against human breast cancer cell line (MCF-7) and then tested in vitro aromatase assay. Two of these newly synthesized compounds exhibited similar activity to letrozole²⁸.

Zhang L et al used in silico analysis and found a small molecule compound targeting Atg4B (Flubendazole), and identified this compound could induce autophagic cell death involved with ROS production. Flubendazole binds to the interacted surface of Atg4B and LC3, so it may regulate the Atg4-LC3 signaling. These findings would advance our understanding of the efficacy of Atg4B target treatment in TNBC therapy. Moreover, it would also provide a basis for developing more Atg4 target agonists in future cancer therapeutics²⁹.

Hsieh CY et al synthesized and examined a new series of N-substituted benzimidazole derivatives with a functional chalcone group. Based on the MTT assay against A549, MCF-7, HEP-G2 and OVCAR-3 cells, they confirmed that these derivatives exhibit considerable potential as anticancer drugs. In particular, compound (2E)-1-(1-(3-morpholinopropyl)-1Hbenzimidazol-2-yl)-3-phenyl-2-propen-1-one) attained high IC50 values on A549, MCF-7, HEP-G2 and OVCAR-3 cells, and showed in vitro cytotoxicity comparable or superior to that of cisplatin³⁰.

Reddy TS et al synthesized a series of pyrazole-benzimidazole hybrids and investigated their antiproliferative activities on four different human tumor cell lines. The results reveal most of the synthesized compounds significantly inhibited cancer cell proliferation; some with superior antiproliferative activity than 5-fluorouracil. Many Compounds showed potent broad spectrum cytotoxic activity against all tested cancer cell lines. The compounds inhibit in vitro cell migration, possibly through restoration of E-cadherin, β-catenin expression and inhibit the long term colonogenic survival of MCF-7 cells. Moreover, the compounds induces G1 phase cell cycle arrest in MCF-7 cells through down regulation of cyclin D1 as well as CDK2. Therefore, these results suggest that the pyrazolyl-benzimidazole hybrids could be targets for further optimization and development of anticancer agents to treat breast cancer³¹.

Abdelgawad MA et al synthesized and evaluated a new series of benzimidazole substituted pyrazole derivatives as antiproliferative agents. They found that a compound 2-acetyl-4- [(3-(1H-benzimidazol-2-yl)phenyl]hydrazono -5-methyl-2,4-dihydropyrazol-3-one was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC50) = 6.42 and 8.46 µM, respectively³².

Singh R et al synthesized and evaluated a library of C6‐substituted benzimidazo [1,2‐a] quinoxaline analogs. The preliminary anticancer screening on the NCI‐60 panel has identified new compounds that showed significant activity against several cancer cell lines. Two of the compounds exhibited significant activities against MCF‐7 breast cancer cell lines, and two compounds demonstrated meaningful activity against a TNBC cell line, MDA‐MB‐ 468. These compounds were also found to be nontoxic to normal cells, providing a rationale to explore more analogs of this class in order to develop more potent anticancer drugs³³.

Patil R et al identified a bisbenzimidazole analog as an initial hit compound to develop novel V-ATPase inhibitors through virtual screening. Synthesis and anticancer evaluation study of a particular set of novel bisbenzimidazole derivatives demonstrated that these compounds have interesting activity against selected breast and ovarian cancer cell lines in vitro. The selected bisbenzimidazole analogs showed selective potency towards the TNBC cell line, MDA-MB-468. Their findings suggests that the bisbenzimidazole analogs could be further developed as an anticancer vacuolar (H+)-ATPase inhibitor for breast cancer therapy³⁴.

Sharma Pankaj et al synthesized a new series of (E)-benzo[d]imidazol-2-yl) methylene) indolin-2-ones hybrids and evaluated for their in vitro cytotoxic potential against different human cancer cell lines including normal breast epithelial cells. The preliminary studies have given away that a few of the synthesized hybrids were active on all the tested cancer cell lines with less than 50 µM (IC50 value). Many compounds were found to be safer with lesser cytotoxicity on normal breast epithelial cells (MCF10A). The cytotoxicity profile revealed that one of the compound displayed broad spectrum of cytotoxic activity against all the tested cancer cell lines. The exposure of MDA-MB-231 cancer cells to this compound inhibited the in vitro cellular migration through the disruption of cytoskeleton and arrested the cells in G0/G1 phase of the cell cycle. Overall, these findings propose that (E)-benzo[d]imidazol-2- yl) methylene) indolin-2-one hybrids have the potential to be developed as lead molecule and further their structural modification may create promising new anticancer agents³⁵.

Kumar A et al synthesized and evaluated a number of tetracyclic benzimidazole derivatives. All synthesized compounds were screened in vitro for antiproliferative activity against five human cancer cell lines: breast T47D, lung NCl H-522, colon HCT-15, ovary PA-1, breast T47D. All compounds exhibited good anticancer activity with IC50 value ranging from 7.5 ± 0.3μM to 14.6 ± 0.4μM³⁶.

Vashist N. et al synthesized a series of substituted benzimidazole compounds and evaluated for their anticancer activity using the SRB assay. These compounds elicited antiproliferative activity against MCF7 breast cancer cell line, which was comparable to the standard drug. The anticancer screening results revealed that few compounds have appreciable activity against MCF7 and their IC50 values were more potent than the standard drug 5-fuorouracil³⁷.

Xu XL et al synthesized a number of novel 1-((indol-3-yl) methyl)–1Himidazolium salts proved to be potent antitumor agents. Compounds bearing a substituted benzimidazole ring, and 4-bromophenacyl or naphthylacyl substituent at position-3 of the benzimidazole ring, were found to be the most potent. One of the compound was found to have the most potent derivative and more selective towards myeloid liver carcinoma (SMMC7721), lung carcinoma (A549) and breast carcinoma (MCF-7), with IC50 values 1.9-fold, 1.7-fold and 4.8-fold lower than DDP. Their findings suggested that the 1-((indol-3-yl) methyl)–1H-imidazolium salts may act as promising leads for further development of novel anticancer agents³⁸.

Paul K et al synthesized some novel coumarin–benzimidazole hybrids as antitumor molecules. In the preliminary biological activity study one of the compound with the introduction of ethanolamine at position-7 of coumarin–benzimidazole hybrid exhibited higher selectivity against leukemia cancer cells (CCRF-CEM, HL-60(TB), K-562, RPMI-8226), colon cancer cells (HCT-116, HCT-15), melanoma cancer cells (LOX IMVI, UACC-257) and breast cancer cells (MCF7, T-47D). Molecular docking study also supported the activity. These compounds could be useful templates templates for the synthesis of potent antitumor agents³⁹.

Łukowska-Chojnacka E et al synthesized and evaluated some new cyanoalkyl polybrominated benzimidazole derivatives. Their cytotoxicity against human CCRF-CEM and MCF-7 cancer cell lines and inhibitory activity against recombinant protein kinase catalytic subunit rhCK2a as well as intracellular inhibition of CK2 were determined. Some of the synthesized compounds showed significant inhibitory activity toward rhCK2 comparable with TBBi. Almost all compounds exhibited significant and comparable cytotoxicity against CCRF-CEM (cell viability up to 7%) and against MCF-7 (cell viability from 5 to 43%). All newly synthesized polybrominated benzimidazole derivatives induced apoptosis in CCRF-CEM cells⁴⁰.

Mochona B et al synthesized a series of hybrid of benzimidazoles containing 1,3,4-oxadiazole pharmacophore that exhibited moderate cytotoxic activities against breast tumor cell lines. The possible explanation of activity is some sort of synergism between benzimidazole coupled with 1,3,4-oxadiazole molecule⁴¹.

Starcević K et al synthesized a set of heterocyclic benzimidazole derivatives bearing amidino substituents at C-5 of benzimidazole ring, by introducing various heterocyclic nuclei at C-2. The results confirmed that novel 2-substituted-5-amidino-benzimidazoles have antitumor potentials. The most pronounced antiproliferative activity was shown with compounds having imidazolinylamidino-substituent. Interestingly, all compounds show selectivity toward breast cancer cell line (MCF-7)⁴².

CONCLUSION:

Benzimidazole ring is an important fused heterocyclic nucleus that can target diverse cancer scenarios as it is structurally similar to biomolecules in the human body. Additionally, output of many studies suggest the involvement of this moiety on a plethora of pathways and enzymes involved in breast cancer. Herein, our target-based collection of benzimidazole derivatives strongly support that the benzimidazole nucleus could be a most promising target for the design and development of novel therapeutic agents against breast cancer with improved efficacy, selectivity and reduced toxicity.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Teerthanker Mahaveer University for their kind support during literature search.

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Received on 02.09.2022 Modified on 24.12.2022

Asian J. Research Chem. 2023; 16(4):303-310.

DOI: 10.52711/0974-4150.2023.00050