Design, synthesis, and biological evaluation of azole antifungals against multidrug-resistant Candida auris

Invasive fungal infections cause over one million deaths annually, with the emerging multidrug-resistant pathogen Candida auris posing a major therapeutic challenge. Here, we report a series of structurally simplified fluconazole analogues designed to retain antifungal potency through targeted scaffold optimisation. The design strategy involved incorporation of a short heteroaliphatic linker, and replacement of one triazole ring with a substituted phenyl moiety to enable controlled modulation of lipophilicity and target interactions. Eighteen compounds were synthesised with calculated log P values of 2.36-3.61 and evaluated against eight C. auris isolates from multiple clades, alongside other clinically relevant Candida species. Several mono- and di-halogenated analogues showed marked potency gains over fluconazole, with MICs as low as 0.03 μg mL^-1 against C. auris and ≤0.008 μg mL^-1 against C. albicans, representing up to 512-fold improvements. Molecular docking supported enhanced binding to lanosterol 14α-demethylase (LDM) via engagement of a hydrophobic sub-pocket. Representative compounds displayed low in vivo toxicity in the Galleria mellonella model at 20 mg kg^-1, and compounds 3 and 18 significantly improved survival in C. auris-infected larvae at 10 mg kg^-1, whereas fluconazole showed no significant efficacy at up to 50 mg kg^-1. These results demonstrate that rational modification of fluconazole scaffold can yield modified azoles with quantitatively improved activity against C. auris and other multidrug-resistant Candida species.