title: ProTides of N-(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents.
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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: mcguigan@cf.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Blanka
authors.initials: B
authors.lastname: Gonczy
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Hinsinger
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Kandil
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Serpi
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Centre for Clinical Microbiology, Research Department of Infection, Royal Free Campus, University College London, Pond Street, London NW3 2QG, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McHugh
authors.affiliation: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Akorli
authors.affiliation: 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.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Evangelopoulos
authors.affiliation: Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Bhakta
mesh_terms: D000577:Amides / Q000737:chemistry*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D003857:Deoxyuridine / Q000737:chemistry*; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D000998:Antiviral Agents; D001426:Bacterial Proteins; D013940:Thymidylate Synthase; D003857:Deoxyuridine
keywords: Anti-tuberculars; Nucleoside analogues; Phosphate prodrugs; Thymidylate synthase X (ThyX); Tuberculosis (TB)