Abstract
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 IC50 values were higher than the MIC50 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.
Highlights
In recent times, the emergence of pathogenic fungi resistant to commonly used antifungal drugs has been occurring at unprecedented rates[1]
Chalcogenides were synthesized in a reaction of KeP with a stoichiometric amount of H2O2, resublimed sulphur or metallic selenium in the ultrasound bath[34,44,45,48]
All compounds tested are substrates for pumps expelling drugs from C. albicans cells, and simultaneous administration of fluconazole allowed a significant reduction in concentrations of ketoconazole derivatives tested and low survival of the fungus
Summary
The emergence of pathogenic fungi resistant to commonly used antifungal drugs has been occurring at unprecedented rates[1]. The search for new antifungals and alternative therapies has become increasingly important To tackle this problem from a medicinal chemistry perspective, and considering that a modification of existing drugs is more straightforward than developing a new class of therapeutic agents, we chose ketoconazole (Ke), a synthetic imidazole antifungal drug approved by FDA in 19818, as a starting molecule for our present study. A long time has passed since the first reports[33], aminomethylphosphanes (or α-aminophosphanes) have been not considered interesting as potential drugs or components of biologically active metal complexes until the last decade. Due to their flexibility and diversity, combined with the ease of synthesis, they started to gain a great attention These compounds can bear an almost infinite variety of substituents with different hydrophilicities and steric demands. We present the synthesis and characteristics of the diphenylphosphanomethyl derivative of ketoconazole and its chalcogenide derivatives (oxide, sulphide and selenide) in order to understand better the influence of a diphenylphosphanometyl(chalcogenide) moiety on the activity of the ketoconazole molecule
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