2. Academic Validation
  3. Design, synthesis, and anticancer evaluation of benzimidazole and benzothiazole derivatives targeting Hsp70 and FoxM1

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

  • Bioorg Med Chem Lett. 2025 Sep 10:130:130401. doi: 10.1016/j.bmcl.2025.130401.
Zahra Alimardan 1,  Khosrow Kashfi 2,  Maryam Abbasi 3,  Ghadamali Khodarahmi 4
Affiliations

Affiliations

  • 1 School of Medicine, Arak University of Medical Sciences, Arak, Iran; School of Health, Arak University of Medical Sciences, Arak, Iran; Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
  • 2 Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, USA; Department of Chemistry and Physics, State University of New York at Old Westbury, New York, USA. Electronic address: kashfi@med.cuny.edu.
  • 3 Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
  • 4 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: khodarahmi@pharm.mui.ac.ir.
PMID: 40939706 DOI: 10.1016/j.bmcl.2025.130401
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.

Keywords

Benzimidazole; Benzothiazole; Cancer therapy; Cytotoxicity; FoxM1; Hsp70; Molecular docking.

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