Tambjamines as Promising Leads for the Development of Next-Generation Antifungals against <i>Candida auris</i>

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 <i>Candida auris</i>. 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 <i>in vitro</i> activity against <i>C. albicans</i> and <i>C. auris</i> at low micromolar concentrations. Among them, the antimalarial lead TA, KAR1123 (<b>15</b>), exhibited marked antifungal activity against both strains, with superior inhibition of <i>C. auris</i>, 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 <i>C. auris</i> and establishes a promising foundation for the development of next-generation antifungal agents targeting MDR fungal pathogens.