ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents

McGuigan, Christopher, Derudas, Marco, Gonczy, Blanka, Hinsinger, Karen, Kandil, Sahar, Pertusati, Fabrizio, Serpi, Michaela, Snoeck, Robert, Andrei, Graciela, Balzarini, Jan, McHugh, Timothy D, Maitra, Arundhati, Akorli, Ernest, Evangelopoulos, Dimitrios and Bhakta, Sanjib (2014) ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents. Bioorganic and Medicinal Chemistry, 22 (9). pp. 2816-2824. ISSN 0968-0896

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The flavin-dependent thymidylate synthase X (ThyX), rare in eukaryotes and completely absent in humans, is crucial in the metabolism of thymidine (a DNA precursor) in many microorganisms including several human pathogens. Conserved in mycobacteria, including Mycobacterium leprae, and Mycobacterium tuberculosis, it represents a prospective anti-mycobacterial therapeutic target. In a M. tuberculosis ThyX-enzyme inhibition assay, N-(3-(5-(2′-deoxyuridine-5′-phosphate))prop-2-ynyl)octanamide was reported to be the most potent and selective 5-substituted 2′-deoxyuridine monophosphate analogue. In this study, we masked the two charges at the phosphate moiety of this compound using our ProTide technology in order to increase its lipophilicity and then allow permeation through the complex mycobacterial cell wall. A series of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide phosphoroamidates were chemically synthesized and their biological activity as potential anti-tuberculars was evaluated. In addition to mycobacteria, several DNA viruses depend on ThyX for their DNA biosynthesis, thus these prodrugs were also screened for their antiviral properties.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Depositing User: Marco Derudas
Date Deposited: 22 Jul 2015 15:05
Last Modified: 28 Oct 2019 16:47
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