Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase. - Archive ouverte HAL Access content directly
Journal Articles ChemMedChem Year : 2006

Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase.

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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.

Dates and versions

pasteur-00166946 , version 1 (13-08-2007)

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Ineke van Daele, Hélène Munier-Lehmann, Pieter M S Hendrickx, Gilles Marchal, Pierre Chavarot, et al.. Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase.. ChemMedChem, 2006, 1 (10), pp.1081-90. ⟨10.1002/cmdc.200600028⟩. ⟨pasteur-00166946⟩

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