Ergosterol-Dependent Membrane Stress and Calcineurin-HSP90 Signaling Govern Fluorinated Sulfone-Induced Cell Death in Candida Albicans

The antifungal activity of halogenated methyl sulfones depends on both the type and number of halogen atoms in the halogenomethylsulfonyl moiety. In this study, 28 halogenomethylphenyl sulfones were evaluated for minimal inhibitory (MIC) and fungicidal concentrations (MFC) against Candida albicans. Active compounds were further tested for cytotoxicity in vitro using the Vero E6 cell line. Notably, 4-(4-chloro-3,4-dichlorophenoxy)-2-nitrophenyl difluoromethyl sulfone (compound 15) showed fungicidal activity while remaining non-toxic at effective doses. Additionally, no adverse effects were observed in Galleria mellonella larvae treated with 15 in vivo. Mechanistic studies with 15 at a sub-inhibitory concentration (2 μg/mL) showed predominant induction of necrosis in C. albicans cells (88.43