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

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

  • Bioorg Med Chem. 2014 May 1;22(9):2816-24. doi: 10.1016/j.bmc.2014.02.056.
Christopher McGuigan 1,  Marco Derudas 2,  Blanka Gonczy 2,  Karen Hinsinger 2,  Sahar Kandil 2,  Fabrizio Pertusati 2,  Michaela Serpi 2,  Robert Snoeck 3,  Graciela Andrei 3,  Jan Balzarini 3,  Timothy D McHugh 4,  Arundhati Maitra 5,  Ernest Akorli 5,  Dimitrios Evangelopoulos 6,  Sanjib Bhakta 5
Affiliations

Affiliations

  • 1 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: mcguigan@cf.ac.uk.
  • 2 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
  • 4 Centre for Clinical Microbiology, Research Department of Infection, Royal Free Campus, University College London, Pond Street, London NW3 2QG, UK.
  • 5 Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
  • 6 Centre for Clinical Microbiology, Research Department of Infection, Royal Free Campus, University College London, Pond Street, London NW3 2QG, UK; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
PMID: 24690527 DOI: 10.1016/j.bmc.2014.02.056
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.

Keywords

Anti-tuberculars; Nucleoside analogues; Phosphate prodrugs; Thymidylate synthase X (ThyX); Tuberculosis (TB).

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