Discovery of Novel Ligands for the Treatment of Cryptococcus neoformans Infection

Fungal pathogens are an escalating global public health concern, particularly in the context of invasive and opportunistic infections. Cryptococcosis, primarily caused by Cryptococcus neoformans var. grubii, can affect multiple organs and often leads to life-threatening meningitis in immunocompromised individuals. Given limited antifungal therapies and emergence of resistance and toxicity-related constraints, the development of novel anti-cryptococcal agents remains an urgent priority. A library of innovative 3-hydroxypyridin-4(1H)-one-based hybrids (5a-f) was synthesized and evaluated for antimicrobial activity against clinically relevant Gram-positive and Gram-negative bacteria, as well as fungal species Candida albicans and C. neoformans var. grubbi. Safety was assessed through cytotoxicity studies in HEK293 and HepG2 cells and hemolytic evaluation, while iron-chelating capacity and lipophilicity were also investigated. All compounds formed stable iron(III) complexes and displayed no significant toxicity up to 25 μM. Series 1 compounds (5a-c) were less lipophilic than Series 2 (5d-f), mainly due to regioisomeric position of hydroxyl group on 2-methyl-4-pyridone scaffold, whereas fluorination increased lipophilicity in both series. Notably, compounds 5c-f emerged as potent, selective, and nontoxic antifungal agents against C. neoformans var. grubii (MIC < 16 µg/mL; CC₅₀ > 32 µg/mL; HC₁₀ > 32 µg/mL), highlighting the potential of 3-hydroxypyridin-4(1H)-one-based hybrids as a promising approach for cryptococcal meningitis therapy.