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 (MIC = 1-2 μg mL), (MIC = 0.5-1 μg mL), and multidrug-resistant (MIC = 2-4 μg mL), outperforming fluconazole and matching amphotericin B. Additionally, compound 35 showed minimal cytotoxicity (88% cell viability at 16 μg mL) and negligible hemolytic activity, indicating a superior safety profile.