Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents

Abstract

In an effort to develop novel azole antifungals with potent activity and high selectivity, a series of (2R,3R)-3-((3-substitutied-phenyl-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previously work. All compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and Cryptococcus neoformans H99, but inactive against Aspergillus fumigatus 7544. Among them, the most active compound 10h displayed outstanding antifungal activity against fluconazole-resistant C. albicans 103, C. glabrata 537 and C. auris 922 with MIC values of ≤0.008 μg/mL. In addition, compound 10h was superior to FLC in inhibiting the filamentation of FLC-resistant C. albicans 103. Notably, compound 10h showed no inhibition of human CYP3A4 with IC50 values of >100 μM, low cytotoxicity at 32 μg/mL and low hERG inhibition with IC50 values of 6.22 μM, suggesting a low risk of drug-drug interactions and good safety profiles. Furthermore, compound 10h exhibited excellent PK profiles and showed remarkable in vivo efficacy in a mouse model of C. albicans and C. neoformans infection. Taken together, compound 10h will be further investigated as a promising lead antifungal agent.