Synthesis of Novel 1,2,3-Triazole Derivatives via Click Chemistry and Evaluation of Their Antifungal Activity

Abstract

Due to clinical demands, there remains a need for new triazole antifungal compounds to broaden the antifungal spectrum and enhance therapeutic efficacy. In this paper, we have developed an effective method for obtaining triazole compounds with 1,2,3-triazole groups introduced into their side chains via click chemistry, targeting the active site of cytochrome P450 14α-demethylase (CYP51). In vitro antifungal activity tests of the title compounds against three human pathogenic fungi demonstrated that this class of compounds exhibited good antifungal activity. Notably, compound 2d exhibits superior antifungal activity compared to fluconazole against Candida albicans SC5314 (with the MIC value of ≤ 0.125 μg/mL) and Cryptococcus neoformans 32609 (with the MIC value of 2 μg/mL), meriting further investigation. Molecular docking results indicated that the introduced 1,2,3-triazole rings in the side chains formed π–π stacking interactions with Tyr118 of CYP51, along with additional hydrogen bonds. This paper provides a method for rapidly modifying the side chains of triazole antifungal drugs in the future to obtain compounds with further enhanced activity.