Design, synthesis, and anticancer evaluation of benzimidazole and benzothiazole derivatives targeting Hsp70 and FoxM1

Abstract

A series of novel benzimidazole and benzothiazole derivatives was designed based on the scaffolds of known Hsp70 (VER-155008) and FoxM1 (FDI-6) inhibitors. Molecular docking studies indicated favorable binding affinities to both targets, with several compounds showing strong interactions within the ATPase domain of Hsp70 and the DNA-binding region of FoxM1. The most promising candidates, as identified by docking scores, were synthesized and structurally confirmed using FT-IR, 1H NMR, and 13C NMR spectroscopy. Their cytotoxicity was evaluated against MCF-7, HeLa, and HUVEC cell lines using the MTT assay. Benzothiazole derivatives exhibited greater cytotoxic activity than benzimidazole counterparts. Among them, compound 7d demonstrated the most potent antiproliferative effect, with IC50 values of 10.83 mu M (MCF-7), 12.68 mu M (HeLa), and 106.75 mu M (HUVEC). Molecular dynamics simulations further confirmed the stability of 7d within the FoxM1 binding pocket, supporting its role as a potential FoxM1 inhibitor. While experimental confirmation of dual-target inhibition in cell-based assays is pending, the computational findings suggest that 7d may function as a dual modulator of Hsp70 and FoxM1, warranting further mechanistic investigation.