Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum

Thirty-one novel albaconazole derivatives were designed
and synthesized
based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic
fungi. Among them, tetrazole compound D2 was the most
potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL
against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three
most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed
a lower inhibitory activity in vitro against human
CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug–drug interactions
and QT prolongation. Moreover, with improved pharmacokinetic profiles,
compound D2 showed better in vivo efficacy
than albaconazole at reducing fungal burden and extending the survival
of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.