Design synthesis and pharmacological evaluation of hydroxamic acid containing novel benzimidazole and benzoxazole derivatives as histone deacetylase inhibitors

Abstract

quotBackground: newlineHistone deacetylases (HDACs) are epigenetic regulators that control gene expression by modifying chromatin structure. Among the 18 HDAC isoforms, HDAC6 plays a distinct cytoplasmic role and is overexpressed in various cancers, including lung, breast, and colon malignancies. Hydroxamic acid-based HDAC inhibitors are particularly effective due to their strong zinc-chelating ability, making them valuable candidates for targeted cancer therapy. newlineObjectives: newlineThe present study aimed to design, synthesize, and evaluate novel benzimidazole and benzoxazole derivatives containing hydroxamic acid moieties as selective HDAC6 inhibitors with potential anticancer properties. newlineMethods: newlineA multistep synthetic protocol was employed to generate hydroxamic acid derivatives incorporating benzimidazole and benzoxazole scaffolds. Characterization was conducted using IR, NMR (^1H, ^13C), and mass spectrometry. Structure activity relationship (SAR) studies were carried out to correlate molecular features with biological activity. In vitro pharmacological assays evaluated HDAC6 inhibition potency and anticancer efficacy on selected cell lines. newlineResults: newlineSeveral synthesized analogs displayed different levels of HDAC6 inhibition, the most active being the para-substituted electron-withdrawing groups. Substituted 4-cyano (ARM513, ARM602) and 4-nitro (ARM512, ARM603) compounds displayed the lowest ICand#8325;and#8320; values, which translates to increased potency, especially in the benzimidazole class. The halogen substitutions 4-chloro and 4-fluoro displayed moderate activity, while 4-bromo derivatives were mostly inactive. Donor groups such as methyl and methoxy led to decreased activity, though para-hydroxy substitution (ARM605) was better. All these observations indicate the impact of electronic effects and substitution patterns on inhibitory activity against HDAC6. newlineConclusion: newlineThe integration of benzimidazole and benzoxazole backbones with hydroxamic acid functionality resulted in a new class of potent, selective HDAC6 inhibitors.