Click synthesis of pyrrolidine-based 1,2,3-triazole derivatives as antifungal agents causing cell cycle arrest and apoptosis in Candida auris.

Autor: Younus Wani M; Department of Chemistry, College of Science, University of Jeddah, 21589 Jeddah, Saudi Arabia. Electronic address: mwani@uj.edu.sa., Saeed Saleh Alghamidi M; Department of Chemistry, College of Science, University of Jeddah, 21589 Jeddah, Saudi Arabia., Srivastava V; Department of Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, South Africa., Ahmad A; Department of Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, South Africa; Infection Control, Charlotte Maxeke Johannesburg Academic Hospital National Health Laboratory Service, South Africa., Aqlan FM; Department of Chemistry, College of Science, University of Jeddah, 21589 Jeddah, Saudi Arabia., Saad Al-Bogami A; Department of Chemistry, College of Science, University of Jeddah, 21589 Jeddah, Saudi Arabia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Jul; Vol. 136, pp. 106562. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1016/j.bioorg.2023.106562
Abstrakt: The emergence of multidrug-resistant fungal pathogens such as Candida auris is one of the major reasons WHO has declared fungal infections as a public health threat. Multidrug resistance, high mortality rates, frequent misidentification, and involvement in hospital outbreaks of this fungus demand the development of novel therapeutic drugs. In this direction, we report the synthesis of novel pyrrolidine-based 1,2,3-triazole derivatives using Click Chemistry (CC) and evaluation of their antifungal susceptibility against C. auris following Clinical and Laboratory Standards Institute (CLSI) guidelines. The fungicidal activity of the most potent derivative (P6) was further quantitatively confirmed by the MUSE cell viability assay. For insight mechanisms, the effect of the most active derivative on cell cycle arrest was studied using Muse TM Cell Analyzer and apoptotic mode of cell death was determined by studying phosphatidylserine externalization and mitochondrial depolarization. In vitro susceptibility testing and viability assays showed that all the newly synthesized compounds have antifungal activity with P6 being the most potent derivative. Cell cycle analysis revealed that P6 arrested the cells in S-phase in a concentration dependent manner and the apoptotic mode of cell death was confirmed by the movement of cytochrome c from mitochondria to cytosol with membrane depolarization. The hemolytic assay confirmed the safe use of P6 for further in vivo studies.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohmmad Younus Wani reports a relationship with University of Jeddah that includes: employment.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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