Antifungal Activity of 8-Hydroxyquinoline Derivatives Against Candida auris, Candida haemulonii, Cryptococcus neoformans, and Cryptococcus gattii Complex

Invasive fungal infections and the emergence of antifungal resistance pose significant challenges to public health. This study evaluates the antifungal activity of two 8-hydroxyquinoline derivatives, PH265 and PH276, against <i>Cryptococcus</i> spp., <i>Candida auris</i>, and <i>Candida haemulonii</i>. Using the EUCAST protocol, both compounds demonstrated broad-spectrum antifungal activity, with MICs ranging from 0.5 to 8 μg/mL. PH276 exhibited synergistic effects with fluconazole and caspofungin against <i>C. haemulonii</i> (FIC ≤ 0.5). The derivatives inhibited <i>C. neoformans</i> biofilm formation at higher concentrations and modulated polysaccharide capsule formation in <i>Cryptococcus</i> spp. In vivo toxicity assays in <i>Tenebrio molitor</i>, <i>Galleria mellonella</i>, and <i>Caenorhabditis elegans</i> revealed no significant adverse effects, with survival rates comparable to controls. These findings highlight PH265 and PH276 as promising antifungal agents with biofilm-disrupting properties, capsule-modulating effects, and low toxicity, supporting their potential for therapeutic development.