Synthesis, molecular docking and biological activity assessment of novel 1,3,4-oxadiazole derivatives as broad-spectrum antifungal candidates

Abstract

The presence of fungistatic properties and potential resistance issues associated with current azole drugs have created a growing demand for discovering novel antifungal agents without these negative attributes. This study introduces the synthesis of a unique series of 4-(5-(benzylthio)-1,3,4-oxadiazol-2-yl) phenol derivatives. Through this approach, we identified promising 1,3,4-oxadiazole-based antifungal candidates with broad-spectrum activity compared with the reference drug fluconazole (FLC). Notably, compounds 5e and 5n displayed the most favorable broad-spectrum antifungal activity among the synthesized derivatives. Compound 5e, displaying low SMIC90 values against all tested resistant isolates, markedly reduced the metabolic activity of mature biofilms formed by FLC-resistant clinical C. albicans and A. flavus isolates in vitro. In cytotoxicity assays, compound 5e showed concentration-dependent effects on mammalian cell viability, with an IC50 of approximately 47 µg mL−1 in HepG2 cells and >60 µg mL−1 in MCF-10A cells, supporting a preliminary selectivity profile relative to its antifungal MIC range. Time-kill studies revealed that the synthesized compounds operate with concentration-dependent reduction in viable fungal counts. Additionally, we conducted an in-depth analysis of the structure–activity relationship (SAR) and molecular interactions with the putative fungal target CYP51 through docking studies, along with evaluating their physicochemical and pharmacokinetic properties. In conclusion, this research underscores the potential of compound 5e as a promising candidate for further investigation as a non-classical antifungal agent.