New Generation Modified Azole Antifungals against Multidrug-Resistant .

The rise of antifungal resistance and limited treatment options highlight the urgent need for new drug classes. is a serious global health threat with few effective therapies. In this study, novel azole-based compounds were developed by modifying the azole core with cyclic heteroaliphatic linkers connecting aromatic and heteroaromatic rings. Several compounds showed potent activity against , including azole-resistant strains, with MICs ranging from 0.016 to 4 μg/mL. The compounds also demonstrated strong activity against , , , and , with MICs mostly below 1 μg/mL. Compounds , , and were more potent than fluconazole. Compound inhibited CYP51, eradicated biofilms, and showed better intracellular accumulation than fluconazole. studies in and confirmed efficacy at 5 mg/kg and no toxicity up to 50 mg/kg, supporting further development of this scaffold against multidrug-resistant infections.