Triazoles have demonstrated significant efficacy in thetreatmentof fungal infections. However, increasing drug resistance is a growingconcern that negatively impacts their effectiveness. By designinga well-crafted side chain, triazoles can be endowed with advantages,like higher potency and the ability to overcome drug resistance. Thishighlights the diverse interactions between side chains and CYP51.To explore novel triazole antifungal agents, we synthesized threeseries of fluconazole-core compounds and focused on optimizing thechain based on molecule docking and in vitro results. The most potent S-F24 exhibited excellent broad-spectrumantifungal activity that was better or comparable to clinically usedazoles. S-F24 maintained its potencyeven against multi-resistant Candida albicans. Additionally, S-F24 displayed a goodsafety profile with high selectivity, low hemolytic effects, and lowtendency to induce resistance. Our findings collectively demonstratedthat there was still a high potential for side-chain modificationin the development of novel azoles.
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