Optimization of (Dithioperoxo)thiolate-Based Antifungal Agents for Triazole-Resistant Aspergillus Fumigatus.

This investigation on novel antifungal agents featuring a thiol-reactive (dithioperoxo)thiolate chemical nucleus [-NC(S)S-SR] established that the optimal levels of fungal growth inhibition were achieved with thiomethyl-bound derivatives (R = Me). The most efficacious analogs had MIC50/MIC90 values of 2/2 µg/mL and an MIC range of 1 to 2 µg/mL for a ten-member panel of voriconazole-resistant A. fumigatus mutants. Pharmacodynamic studies revealed that the lead (dithioperoxo)thiolates impaired conidial germination and germling development more effectively than voriconazole for the triazole-resistant strain AR-1295. Moreover, glutathione and Cu2+ were shown to have antagonistic interactions, which was attributed to the thiol-reactive, pro-oxidant properties of the (dithioperoxo)thiolates and their metabolic conversion to chelating agents. Cytotoxicity studies further showed that the compounds were less toxic to human fetal kidney cells than squamous carcinoma cells. The collective findings of the investigation indicate that (dithioperoxo)thiolates are effective antifungal agents against A. fumigatus to merit additional research on their therapeutic potential.