Four bis (benzimidazole) derivatives featuring different linkers, imino methyl (Ambmz), pyridine (Pybmz), ethene (Etbmz), and phenyl (Phbmz), were synthesized and investigated for their anticancer potential against human breast cancer (MCF-7) cells. The nature of the linker was found to play a decisive role in modulating the biological activity of these compounds. Cytotoxicity assays showed that Etbmz exhibited the most pronounced growth-inhibitory effect, followed by Pybmz and Ambmz, whereas Phbmz exhibited prolonged anticancer activity as evident by the conony assay. Further to understand their mechanism of interaction with human DNA Topoisomerase I (hTopo I), the DFT calculations, molecular docking, and 200-ns molecular dynamics (MD) simulations were performed. The docking and MM-GBSA analyses revealed strong and stable binding affinities (ΔGbind ≈ − 74 to − 77 kcal/mol), mainly governed by van der Waals and electrostatic interactions. The strong correlation between the computational findings and experimental cytotoxicity highlights the importance of linker flexibility and electronic features in determining enzyme inhibition. Overall, Etbmz emerges as a promising lead compound for the design of new benzimidazole-based anticancer agents targeting hTopo I.
Mahitha et al. (Wed,) studied this question.