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 logP 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 against C. auris and ≤0.008 µg/mL 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, and compounds 3 and 18 significantly improved survival in C. auris-infected larvae at 10 mg/kg, whereas fluconazole showed no significant efficacy at up to 50 mg/kg. 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.

© 2026 The Author(s). Published by the Royal Society of Chemistry
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