New diphenylphosphane derivatives of ketoconazole are promising antifungal agents

• Published in: Scientific reports Vol. 9; no. 1; pp. 16214 - 14
• Main Authors: de Almeida, Rodrigo F. M., Santos, Filipa C., Marycz, Krzysztof, Alicka, Michalina, Krasowska, Anna, Suchodolski, Jakub, Panek, Jarosław J., Jezierska, Aneta, Starosta, Radosław
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.11.2019; Nature Publishing Group
• Subjects: 119/118; 13/100; 13/2; 13/44; 14; 14/19; 140/131; 631/326/22/1292; 639/638/309/2144; Adipose Tissue - cytology; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Apoptosis; Apoptosis - drug effects; Azoles; Biphenyl Compounds - chemistry; Candida albicans; Candida albicans - drug effects; Cyclin-dependent kinase inhibitor p21; Cytochrome P450; Cytotoxicity; Drug Synergism; Ergosterol; Fluconazole; Humanities and Social Sciences; Humans; Ketoconazole; Ketoconazole - chemistry; Ketoconazole - pharmacology; Ketoconazole - toxicity; Lanosterol; Membrane potential; Mitochondria; multidisciplinary; p53 Protein; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Science; Science (multidisciplinary); Selenide; Stem Cells - cytology; Stem Cells - drug effects; Stromal cells; Sulfides; Transcription; Yeast
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-52525-7

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.