BSU5(Universidade Federal de Minas Gerais)

Cryptococcus neoformans cause cryptococcal meningitis, particularly in individuals with compromised immune systems. In this context, urease plays a crucial role in fungal survival by facilitating infection spread and penetration of the blood-brain barrier, making this enzyme a potential target for antifungal therapy. Eleven benzoylselenoureas (BSU) were synthesized in 15-75% yields via a one-pot approach using benzoyl chloride, KSeCN, and anilines containing electron-donating or electron-withdrawing groups. The antifungal and urease inhibitory activities of these compounds were evaluated against C. neoformans. For comparison, the corresponding benzoylthioureas (BTU) analogs were also synthesized to assess the influence of the chalcogen atom on biological activity. Antifungal activity was determined using the broth microdilution assay, while urease inhibition was evaluated through ammonia quantification. Additionally, inhibitor-enzyme interactions were investigated using homology modeling, molecular docking, molecular dynamics simulations, and density functional theory (DFT) calculations. The BSU compounds demonstrated higher antifungal activity than their BTU analogs, with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values ranging from 1 to 16 mg/L (except for BSU3, BSU8, and BSU11). The most active compounds against yeast were BSU1 and BSU5, which feature an OMe group at the meta position of the aniline moiety. Furthermore, BSU compounds exhibited strong urease inhibition, with ureIC₅₀ values ranging from 0.95 to 13.95 nM. Computational studies revealed that BSU compounds predominantly coordinate with the Ni-(II) center in a bidentate mode, likely involving the amide oxygen and selenium atoms. These findings indicate that BSU compounds effectively inhibit urease activity and C. neoformans growth at low concentrations, reinforcing urease as a promising target for antifungal therapy. Molecular modeling confirmed the strong affinity of BSU compounds for urease, supporting their potential as novel antifungal agents.