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

McGuigan, Christopher ORCID:, Derudas, Marco, Gonczy, Blanka, Hinsinger, Karen, Kandil, Sahar ORCID:, Pertusati, Fabrizio ORCID:, Serpi, Michaela ORCID:, 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. 10.1016/j.bmc.2014.02.056

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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
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Tuberculosis (TB); Thymidylate synthase X (ThyX); Phosphate prodrugs; Nucleoside analogues; Anti-tuberculars
Additional Information: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License
Publisher: Elsevier
ISSN: 0968-0896
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 28 February 2014
Last Modified: 18 May 2024 17:33

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