Tambjamines as Promising Leads for the Development of Next-Generation Antifungals against Candida auris.

Human fungal infections pose a major global health challenge, underscoring the urgent need for new chemotypes that are effective against multidrug-resistant (MDR) fungal pathogens such as Candida auris. Tambjamines (TAs), previously characterized for their potent antimalarial and antileishmanial activities, were investigated for their antifungal potential. A selected series of TA analogs exhibited excellent in vitro activity against C. albicans and C. auris at low micromolar concentrations. Among them, the antimalarial lead TA, KAR1123 (15), exhibited marked antifungal activity against both strains, with superior inhibition of C. auris, while displaying favorable cytotoxicity, metabolic stability, and pharmacokinetic properties. Structure-activity relationship analyses highlighted key structural elements required for antifungal potency. Collectively, this study represents the first evidence of TA activity against C. auris and establishes a promising foundation for the development of next-generation antifungal agents targeting MDR fungal pathogens.