In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 μg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.
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