Discovery of highly potent antifungal triazoles by structure-based lead fusion

Abstract

By means of structure-based lead fusion, a series of novel drug-like azoles possessing 4-(benzyloxy)piperidin-1-yl side chains were rationally designed and synthesized. Flexible molecular docking studies indicated that the newly synthesized azoles took advantages of the key interactions between the two lead structures and CACYP51. As a result, they revealed improved antifungal activity and broader spectrum. All the new azoles showed good to excellent in vitro antifungal activity against all of the tested pathogenic fungi (MIC₈₀ range: 2.33–0.01 μM). Compounds 10a, 10g and 10h, the most active azoles toward Candida albicans (MIC₈₀ = 0.01 μM) are 82 fold more potent than fluconazole. In particular, all the compounds also showed good activity against Aspergillus fumigatus (MIC₈₀ = 2.33–0.55 μM) that is not sensitive to fluconazole.