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

Abstract

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent <i>in vitro</i> antifungal activities against seven pathogenic fungi. Among them, tetrazole compound <b>D2</b> was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against <i>Candida albicans</i>, <i>Cryptococcus neoformans</i>, and <i>Aspergillus fumigatus</i>, respectively, the three most common and critical priority pathogenic fungi. In addition, compound <b>D2</b> also exhibited potent activity against fluconazole-resistant <i>C. auris</i> isolates. Notably, compound <b>D2</b> showed a lower inhibitory activity <i>in vitro</i> 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 <b>D2</b> showed better <i>in vivo</i> efficacy than albaconazole at reducing fungal burden and extending the survival of <i>C. albicans</i>-infected mice. Taken together, compound <b>D2</b> will be further investigated as a promising candidate.