Cargando…

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 syner...

Descripción completa

Detalles Bibliográficos
Autores principales: de Almeida, Rodrigo F. M., Santos, Filipa C., Marycz, Krzysztof, Alicka, Michalina, Krasowska, Anna, Suchodolski, Jakub, Panek, Jarosław J., Jezierska, Aneta, Starosta, Radosław
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838151/
https://www.ncbi.nlm.nih.gov/pubmed/31700024
http://dx.doi.org/10.1038/s41598-019-52525-7
_version_ 1783467170934554624
author de Almeida, Rodrigo F. M.
Santos, Filipa C.
Marycz, Krzysztof
Alicka, Michalina
Krasowska, Anna
Suchodolski, Jakub
Panek, Jarosław J.
Jezierska, Aneta
Starosta, Radosław
author_facet de Almeida, Rodrigo F. M.
Santos, Filipa C.
Marycz, Krzysztof
Alicka, Michalina
Krasowska, Anna
Suchodolski, Jakub
Panek, Jarosław J.
Jezierska, Aneta
Starosta, Radosław
author_sort de Almeida, Rodrigo F. M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6838151
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-68381512019-11-14 New diphenylphosphane derivatives of ketoconazole are promising antifungal agents de Almeida, Rodrigo F. M. Santos, Filipa C. Marycz, Krzysztof Alicka, Michalina Krasowska, Anna Suchodolski, Jakub Panek, Jarosław J. Jezierska, Aneta Starosta, Radosław Sci Rep Article 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. Nature Publishing Group UK 2019-11-07 /pmc/articles/PMC6838151/ /pubmed/31700024 http://dx.doi.org/10.1038/s41598-019-52525-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
de Almeida, Rodrigo F. M.
Santos, Filipa C.
Marycz, Krzysztof
Alicka, Michalina
Krasowska, Anna
Suchodolski, Jakub
Panek, Jarosław J.
Jezierska, Aneta
Starosta, Radosław
New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title_full New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title_fullStr New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title_full_unstemmed New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title_short New diphenylphosphane derivatives of ketoconazole are promising antifungal agents
title_sort new diphenylphosphane derivatives of ketoconazole are promising antifungal agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838151/
https://www.ncbi.nlm.nih.gov/pubmed/31700024
http://dx.doi.org/10.1038/s41598-019-52525-7
work_keys_str_mv AT dealmeidarodrigofm newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT santosfilipac newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT maryczkrzysztof newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT alickamichalina newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT krasowskaanna newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT suchodolskijakub newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT panekjarosławj newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT jezierskaaneta newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents
AT starostaradosław newdiphenylphosphanederivativesofketoconazolearepromisingantifungalagents