Discovery of New Pyrazolone Derivatives for Treating Invasive Fungal Infections by Iron Homeostasis Disruption.

Invasive fungal infections caused by Cryptococcus neoformans and Candida glabrata pose a severe threat to global public health due to high mortality, urgently requiring the development of antifungal agents with novel mechanisms. Herein, a series of new pyrazolone derivatives were designed and evaluated. In particular, compound D2 exhibited subnanomolar antifungal activity against Cryptococcus neoformans and Candida glabrata strains (MIC range: 0.00012-0.0078 μg/mL). Mechanistically, compound D2 disrupted fungal iron homeostasis, impaired mitochondrial structure and function, and triggered oxidative stress damage. In addition, compound D2 effectively inhibited virulence factors, including biofilms, capsule, urease, and melanin. In mouse models of cryptococcal meningitis and candidiasis, compound D2 significantly reduced fungal burden and alleviated tissue damage. Thus, compound D2 is a promising lead with dual fungicidal and antivirulence effects, promoting the development of novel iron-targeting antifungals.