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 μM (MCF-7), 12.68 μM (HeLa), and 106.75 μM (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.