New diphenylphosphane derivatives of ketoconazole are promising antifungal agents

Four new derivatives of ketoconazole ( Ke ) were synthesized: diphenylphosphane ( KeP ), and phosphane chalcogenides: oxide ( KeOP ), sulphide ( KeSP ) and selenide ( KeSeP ). These compounds proved to be promising antifungal compounds towards Saccharomyces cerevisiae and Candida albicans , especially in synergy with fluconazole. Simulations of docking to the cytochrome P450 14α-demethylase (azoles’ primary molecular target) proved that the new Ke derivatives are capable of inhibiting this enzyme by binding to the active site. Cytotoxicity towards hACSs (human adipose-derived stromal cells) of the individual compounds was studied and the IC 50 values were higher than the MIC 50 for C . albicans and S . cerevisiae . KeP and KeOP increased the level of the p21 gene transcript but did not change the level of p53 gene transcript, a major regulator of apoptosis, and decreased the mitochondrial membrane potential. Taken together, the results advocate that the new ketoconazole derivatives have a similar mechanism of action and block the lanosterol 14α-demethylase and thus inhibit the production of ergosterol in C . albicans membranes.