New generation modified azole antifungals against multidrug-resistant <i>candida auris</i>

The rise of antifungal resistance and limited treatment options highlight the urgent need for new drug classes. <i>Candida auris</i> 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 C. <i>auris</i>, including azole-resistant strains, with MICs ranging from 0.016 to 4 μg/mL. The compounds also demonstrated strong activity against <i>C. albicans, Nakaseomyces glabratus, C. tropicalis, and C. parapsilosis</i>, with MICs mostly below 1 μg/mL. Compounds 7, 18, and 21 were more potent than fluconazole. Compound 7 inhibited CYP51, eradicated <i>C. auris</i> biofilms, and showed better intracellular accumulation than fluconazole. <i>In vivo</i> studies in <i>Galleria mellonella</i> and <i>Drosophila melanogaster</i> confirmed efficacy at 5 mg/kg and no toxicity up to 50 mg/kg, supporting further development of this scaffold against multidrug-resistant <i>C. auris</i>infections.