Synthesis and antifungal activities of bisbenzazole derivatives

Invasive fungal infections (IFIs) are increasing as major infectious diseases around the world, with existing medications demonstrating limited efficacy, leading to considerable morbidity and mortality due to the absence of potent antifungal agents and the emergence of serious drug resistance. In this study, a series of bisbenzazole derivatives, featuring a methyl thio linker and either 5-nitro or chloro substituent benzimidazole ring, were synthesized using straightforward and environmentally friendly reaction conditions, and characterized via 1H NMR, 13C NMR, and IR spectral analysis. All synthesized compounds screened in vitro screening for their antifungal activity against two fungal strains, namely, C. albicans and C. parapsilosis. The compounds demonstrated significant antifungal potential, particularly against C. parapsilosis. Furthermore, molecular docking was conducted to ascertain the affinities and potential binding poses of the compounds to the catalytic regions of the target proteins 14α-demethylase (CYP51) and secreted aspartic proteases (Sapps1p). Compounds 13 and 16 exhibited the highest affinity for CYP51, with docking scores of -6.785 and -6.923 kcal/mol, respectively. The compounds' ADMET properties were assessed in silico, revealing favorable physicochemical characteristics.