Title: Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase
Authors: Van Daele, Ineke ×
Munier-Lehmann, Hélène
Hendrickx, Pieter M S
Marchal, Gilles
Chavarot, Pierre
Froeyen, Mathy
Qing, Li
Martins, José C
Van Calenbergh, Serge #
Issue Date: Oct-2006
Series Title: ChemMedChem vol:1 issue:10 pages:1081-90
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.
ISSN: 1860-7179
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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