Repurposing the phenylthiazole scaffold with 1,3,4-oxadiazole for selective, potent and well-tolerated antifungal activity

Invasive fungal infections (IFIs) represent a critical health threat, particularly among immunocompromised individuals, with mortality rates reaching up to 50%. The growing resistance to existing antifungal therapies necessitates the development of novel agents. Here, we rationally designed phenylthiazole-based oxadiazole derivatives to enhance selectivity and potency against resistant fungal strains. Among the tested compounds, compound 35 (which emerged as a lead candidate) demonstrated potent activity against <i>Candida albicans</i> (MIC = 1-2 μg mL^-1), <i>Candida glabrata</i> (MIC = 0.5-1 μg mL^-1), and multidrug-resistant <i>Candida auris</i> (MIC = 2-4 μg mL^-1), outperforming fluconazole and matching amphotericin B. Additionally, compound 35 showed minimal cytotoxicity (88% cell viability at 16 μg mL^-1) and negligible hemolytic activity, indicating a superior safety profile.