Structure-Based Optimization of Triazole-Linked Sesamol Conjugates as Antifungal Agents Targeting CYP51 in Candida albicans.

The increasing prevalence of azole-resistant Candida albicans due to extensive and irrational use of antifungal agents demands the development of new selective and effective antifungal agents. Here, we designed a series of triazole-linked sesamol-based conjugates using an integrated e-pharmacophore and molecular hybridization approach. Compounds were synthesized and evaluated for anti-Candida efficacy against a panel of pathogenic Candida strains. Among them, compound CH3 displayed the highest antifungal efficacy against Candida albicans (MIC = 1.9 μM and MFC = 3.9 μM). CH3 also showed biofilm eradication activity, and drug resistance was not observed in a 30 day resistance induction assay. CH3 was nontoxic and capable of rescuing larvae (G. mellonella) from the Candida-infected larvae model. With a favorable safety profile and desirable potency in both in vitro and in vivo, CH3 is a promising lead molecule for future drug development against Candida infections.