Background and Objective : Drug resistance and adverse effects are immense healthcare challenges in cancer therapy. Benzimidazole ring-based small molecules have been effective anticancer agents in drug development. In an effort to develop novel chemotherapeutics, we synthesized and assessed the anticancer and antibacterial activities of a small library of structurally unique benzimidazoles. Methods : The benzimidazoles were derived from indole, N-alkyl indole, fatty acid, and alpha-amino acid scaffolds providing a panel of diverse structures. The compounds were tested in three different cancer cell lines for cytotoxicity: HepG2 (human hepatocellular carcinoma), HeLa (human cervical carcinoma), and A549 (human lung carcinoma). Mechanism of cell death induced by benzimidazoles was evaluated using fluorescent dye-based apoptosis-necrosis assay, immunoblotting for active caspases, topoisomerase-II activity assay, and cell cycle assay. Results : Cell viability testing revealed that indole- and fatty acid-based benzimidazoles were most potent followed by the amino acid derivatives. Many compounds induced cytotoxicity in a concentration-dependent manner with cellular cytotoxicity (CC50) <20μM in the cell lines tested. Most compounds exhibited cytotoxicity via apoptosis through the intrinsic pathway. Inhibition of topoisomerase activity and cell cycle alterations were not the primary mechanisms of cytotoxicity. In addition, several compounds showed promising activity against S. aureus and S. epidermidis (Minimum Inhibitory Concentration (MIC) of as low as 0.04μmol/mL). Conclusion: The reported benzimidazole derivatives possess promising anticancer and antibacterial properties. Additionally, we discovered apoptosis to be the primary mechanism for cancer cell death induced by the tested benzimidazoles. Our findings suggest that further development of these scaffolds could provide drug leads towards new chemotherapeutics.

Indolylbenzimidazoles have emerged as an important pharmacophore during drug discovery efforts. More specifically, N‐alkylation of indole and/or benzimidazole motifs has been a useful strategy for structure diversification to generate bioactive leads. Herein, we report a simple and efficient methodology for the chemo‐selective N‐alkylation of indolylbenzimidazole scaffolds. This approach takes advantage of the pKa differences between the indole and benzimidazole nitrogen to achieve the desired chemo‐selectivity. Using the reported method, one can readily access a selection of mono‐N‐alkylated or asymmetrically bis‐alkylated indolylbenzimidazole scaffolds in a simple one‐pot operation. Moreover, this method provides the desired products in excellent yield and demonstrates a broad substrate scope.