Design, synthesis, and anticandidal evaluation of benzimidazole and imidazopyridine-based N-Acylhydrazones

A novel series of benzimidazole and imidazo[1,2-a]pyridine-based N-acylhydrazones was designed, synthesized, and evaluated for antifungal activity against a clinical strain of Candida albicans. Structural elucidation was performed using ¹H and ¹³C NMR spectroscopy and High-Resolution Mass Spectrometry (HRMS). In vitro antifungal testing revealed that several compounds exhibited moderate to strong anticandidal activity, with minimum inhibitory concentrations (MICs) ranging from 26.009 µM to 70.034 µM, compared to fluconazole as the reference drug. Structure–activity relationship (SAR) analysis demonstrated that lipophilic aryl substituents, particularly naphthalen-2-ol and aryl sulfane moieties, play a key role in enhancing antifungal efficacy, likely by promoting membrane permeability through increased hydrophobic interactions. Notably, compound 6a, bearing a naphthalen-2-ol fragment, emerged as the most potent derivative. The results highlight the promising potential of N-acylhydrazone scaffolds, particularly those integrating sulfur-containing or polycyclic aromatic groups, as leads for the development of new antifungal agents targeting resistant Candida albicans strains.