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ProTides of N-(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents
journal contribution
posted on 2023-06-08, 21:49 authored by Christopher McGuigan, Marco Derudas, Blanka Gonczy, Karen Hinsinger, Sahar Kandil, Fabrizio Pertusati, Michaela Serpi, Robert Snoeck, Graciela Andrei, Jan Balzarini, Timothy D McHugh, Arundhati Maitra, Ernest Akorli, Dimitrios Evangelopoulos, Sanjib BhaktaThe 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.
History
Publication status
- Published
Journal
Bioorganic and Medicinal ChemistryISSN
0968-0896Publisher
ElsevierExternal DOI
Issue
9Volume
22Page range
2816-2824Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-22Usage metrics
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