ProTides of N–(3-(5-(2’-deoxyuridine))prop-2- ynyl)octanamide as potential anti-tubercular and anti-viral agents
McGuigan, C. and Derudas, M. and Gonczy, B. and Hinsinger, K. and Kandil, S. and Pertusati, F. and Serpi, M. and Snoeck, R. and Andrei, G. and Balzarini, J. and McHugh, T.D. and Maitra, A. and Akorli, E. and 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 & Medicinal Chemistry 22 (9), pp. 2816-2824. ISSN 1464-3391.
Abstract
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.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | Tuberculosis (TB), Thymidylate synthase X (ThyX), Phosphate prodrugs, Nucleoside analogues, Anti-tuberculars |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 17 Mar 2014 09:25 |
| Last Modified: | 02 Aug 2023 17:09 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/9345 |
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