Design, Synthesis, and Inhibitory Activity of Benzimidazole‐2‐thiol Derivatives on SHSY‐5Y Neuroblastoma Cancer Cell Line

Abstract

Neuroblastoma, a prevalent childhood cancer, necessitates the design of more potent and more selective drugs. Benzimidazole derivatives are reported to possess significant anticancer activity in recent investigations. In this report, we designed, synthesized, and tested a new series of benzimidazole‐2‐thiol derivatives targeting the WD repeat‐containing protein 5 (WDR5), particularly its less‐studied WBM (WDR5 binding motif) binding site. 10 derivatives were prepared and characterized by IR, ¹H NMR, ¹³C NMR, and LC–MS. In silico docking and ADMET profiling revealed good binding affinity, pharmacokinetics, and blood–brain barrier permeability. HS‐5G and HS‐5H of the synthesized compounds were found to possess high inhibitory activity against SH‐SY5Y neuroblastoma cells, and high cytotoxicity was reported at 48 h (IC₅₀ = 25 µM). Structure‐activity relationship (SAR) analysis implied the enhancement of activity by dichloro substitutions due to improved hydrophobic interactions and target binding. This research shows one of the earliest examples of benzimidazole‐2‐thiol derivatives that have been designed to inhibit the WBM site of WDR5. The integration of docking‐guided synthesis, favorable ADMET profiles, and compelling in vitro activity places HS‐5G and HS‐5H as prominent lead candidates for further investigation in neuroblastoma treatment.