Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.

Autor: Hamdy R; Research Institute for Medical and Health Sciences, and College of Pharmacy, University of Sharjah, Sharjah, 27272, UAE; Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt., Soliman SSM; Research Institute for Medical and Health Sciences, and College of Pharmacy, University of Sharjah, Sharjah, 27272, UAE; Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address: ssoliman@sharjah.ac.ae., Alsaadi AI; Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovations, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA 90502, USA., Fayed B; Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovations, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA 90502, USA; Chemistry of Natural and Microbial Product Department, National Research Centre, Cairo, Egypt., Hamoda AM; Research Institute for Medical and Health Sciences, and College of Pharmacy, University of Sharjah, Sharjah, 27272, UAE; Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Elseginy SA; Green Chemistry Department, Chemical Industries Research Division, National Research Center, 12622, Egypt; Molecular Modeling Lab., Biochemistry School, Bristol University, Bristol, UK., Husseiny MI; Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010-3000, USA., Ibrahim AS; Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovations, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA 90502, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: ibrahim@lundquist.org.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2020 May 30; Vol. 148, pp. 105327. Date of Electronic Publication: 2020 Apr 06.
DOI: 10.1016/j.ejps.2020.105327
Abstrakt: Candida albicans is a common human fungal pathogen that causes disease ranging from superficial to lethal infections. C. albicans grows as budding yeast which can transform into hyphae in response to various environmental or biological stimuli. Although both forms have been associated with virulence, the hyphae form is responsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selectively inhibit C. albicans hyphae formation without affecting human cells to afford sufficient safety. The newly designed 5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one derivatives, named SR, showed very specific and effective inhibition activity against C. albicans hyphae formation. SR compounds caused hyphae inhibition activity at concentrations 10-40 fold lower than the concentration required to inhibit Candida yeast and bacterial growths. The anti-hyphae inhibition activities of SR compounds were via activation of the hyphae transcription repressor gene, TUP1. Correlation studies between the expression of TUP1 gene and the activity of SR compounds confirmed that the anti-C. albicans activities of SR compounds were via inhibition of hyphae formation. The newly designed SR compounds showed 10-40% haemolytic activity on human erythrocytes when compared to 100% haemolysis by 0.1% triton employed as positive control. Furthermore, theoretical prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of SR compounds confirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity and significant activity of the newly-designed SR compounds, a future optimization of pharmaceutical formulation may develop a promising inhibitor of hyphal formation not only for C. albicans but also for other TUP1- dependent dimorphic fungal infections.
Competing Interests: Declaration of Competing Interest The University of Sharjah has filed intellectual property rights concerning SR compounds.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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