title: Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase.
abstract: Herein we describe the synthesis and conformational analysis of a series of bicyclic thymidine derivatives and their evaluation as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a K(i) value of 2.3 microm, 1-[3-aminomethyl-3,5-dideoxy-2-O,6-N-(thiocarbonyl)-beta-D-ribofuranosyl]thymine emerged as the most potent TMPK inhibitor of this series. Moreover, this promising compound displays inhibitory potency against Mycobacteria cultures with an IC(99) value of 100 microg mL(-1), thus promoting TMPKmt for the first time as a validated target for further inhibitory design. Attempts to rationalise the observed structure-activity relationship (SAR) involving molecular modelling and conformational analysis are described.
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Gent University Harelbekestraat 72, Gent, Belgium.
authors.forename: Ineke
authors.initials: I
authors.lastname: Van Daele
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Pieter M S
authors.initials: PM
authors.lastname: Hendrickx
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.forename: Pierre
authors.initials: P
authors.lastname: Chavarot
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Li
authors.initials: L
authors.lastname: Qing
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009163:Mycobacterium bovis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine