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

Abstract

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 Candida albicans (MIC = 1–2 μg mL⁻¹), Candida glabrata (MIC = 0.5–1 μg mL⁻¹), and multidrug-resistant Candida auris (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.