ChemMedChem. 2006 Oct;1(10):1081-90.

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

Van Daele I, Munier-Lehmann H, Hendrickx PM, Marchal G, Chavarot P, Froeyen M, Qing L, Martins JC, Van Calenbergh S.

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Laboratory for Medicinal Chemistry (FFW), Gent University Harelbekestraat 72, Gent, Belgium.

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.

PMID:: 16921580; [PubMed - indexed for MEDLINE]

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