Design and synthesis of novel CYP51 inhibitors as therapeutics for candida albicans infections

Alsulaimany, Marwa Naser 2022. Design and synthesis of novel CYP51 inhibitors as therapeutics for candida albicans infections. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Lanosterol 14!-demethylase, CYP51, is an important target enzyme in fungal diseases. Candida albicans (C. albicans) is one of the fungal pathogens prevalent in human infections, which causes infections that range from superficial to life-threatening systemic infections, a particular challenge in immunocompromised patients. Although azoles (especially Fluconazole) have been used as a first choice for the treatment in many fungal infections and as a prophylactic, issues of drug resistance to this class of antifungals are increasing. The aim of this study was to design and synthesise novel CYP51 inhibitors that can counteract the azole resistance mechanism in C. albicans. Drug design employed computational methods: Molecular Operating Environment (MOE) for docking and binding studies and Desmond Maestro for Molecular Dynamic (MD) simulations to determine optimal fit in the CaCYP51 active site and binding interactions. From the computational docking study, thiazole, hydroxy-propyl benzamide and non-hydroxypropanamide novel compounds were selected for synthesis; a short series (fluconazole type), a mid-sized and an extended series (posaconazole type), which showed promising docking results. The extended series was observed to have optimal filling of the active site and additional binding interactions (H-bonding and π-π/hydrophobic) at the access channel that were anticipated to counteract the loss of one key H-bonding interaction with Tyr132, a common mutation in C. albicans azole resistant strains (Y132H, Y132F). Using 4-8 step synthetic schemes, all series were obtained and compounds subject to structure (1H and 13C NMR, mass spectroscopy) and purity (HPLC) analysis. All final compounds for the thiazole (Chapter 2 and 3), chloro and dichloro of the hydroxy-propyl benzamide (Chapter 4) were evaluated against C. albicans strains (MIC) and promising compounds evaluated further for CaCYP51 binding affinity (Kd) and inhibitory activity (IC50) in comparison with the standards fluconazole. Owing to the COVID-19 situation, the fluoro and difluoro compounds of the hydroxy-propyl benzamide series (Chapter 4) were screened first against the model organism Saccharomyces cerevisiae wildtype and single mutant strains using disk diffusion assay, and the most promising compounds were progressed for evaluation against C. albicans strains using disk diffusion assay and MIC in comparison with posaconazole. The hydroxy-propyl benzamide extended compounds (Chapter 4) (57, 59, 69 and 70) were found to be active against C. albicans strains. The biological assessment of the non-hydroxy-propanamide compounds (Chapter 5) is still in progress. Those compounds with optimal activity will be further evaluated against CaCYP51 mutant strains as ! xiv well for selectivity against human CYP51. Further testing against a wide range of fungal strain will be done for future work.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	22 February 2022
Last Modified:	21 Feb 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/147691

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