Antifungal activity and toxicity of novel urease inhibitors against Cryptococcus spp.

Cryptococcosis is a mycosis with high incidence in HIV/AIDS patients leading to high mortality. Antifungal molecules are being researched addressing new targets and the urease enzyme could be an interesting candidate. Twenty-six urease inhibitors were tested against Cryptococcus neoformans with evaluation of minimum inhibitory, fungicidal and urease activity concentrations. Among these, the lead compound AF19 was selected based on the best results with inhibition of urease activity, fungal growth, and fungicidal effect against 13 clinical isolates of C. neoformans and C. gattii. AF19 presented low citotoxicity potential in vitro on fibroblast, tumor cells and macrophages, and no hemolytic effect was observed up to 128 μg/mL. On the larval model of Galleria mellonella, the maximal dosage of 100 mg/kg did not result in death or morbidity. Our results indicate the antifungal potential of AF19, however, further assays should be conducted to validate urease as a target and better elucidate its effects.