title: Synthesis and evaluation of 5-substituted 2'-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis.
abstract: A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
authors.affiliation: Katholieke Universiteit Leuven, Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Martin
authors.initials: M
authors.lastname: Kögler
authors.forename: Bart
authors.initials: B
authors.lastname: Vanderhoydonck
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Belle
authors.forename: Jean
authors.initials: J
authors.lastname: Herman
authors.forename: Thierry
authors.initials: T
authors.lastname: Louat
authors.forename: Anastasia
authors.initials: A
authors.lastname: Parchina
authors.forename: Carol
authors.initials: C
authors.lastname: Sibley
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005415:Flavins / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D003856:Deoxyuracil Nucleotides; D005415:Flavins; C561239:N-(3-(5-(2'-deoxyuridine-5'-monophosphate))prop-2-ynyl)octanamide; D013940:Thymidylate Synthase