Design, synthesis, and antifungal activity of novel amide imidazole CYP51 inhibitors with aromatic fused ring hydrophobic side chains

Invasive fungal infections caused by <i>Candida albicans</i> are becoming increasingly severe, creating an urgent need to explore new antifungal drugs. Compound YW01 is a structurally novel CYP51 inhibitor that was screened by our research group in the preliminary stage. To enhance its activity, three rounds of structural optimization and modification were conducted in this study. Through <i>in vitro</i> antifungal activity testing and time-kill curve analysis, it was found that compound B3 exhibited potent antifungal activity, which was superior to that of the positive control drug fluconazole. Further research on the antifungal mechanism revealed that compound B3 could effectively inhibit the yeast-to-hypha transition of <i>Candida albicans</i> and possessed the ability to kill fungi. Cytotoxicity experiments demonstrated that compound B3 had no significant inhibitory effects on MCF-7, A549 and BEAS-2B cell lines, indicating moderate safety. In summary, as a CYP51 inhibitor with a novel structural type, compound B3 is highly worthy of further investigation.