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