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: Ineke Van Daele, Hélène Munier-Lehmann, Pieter M S Hendrickx, Gilles Marchal, Pierre Chavarot, Matheus Froeyen, Li Qing, José C Martins, Serge Van Calenbergh
• Journal: ChemMedChem (ChemMedChem) Vol. 1 Issue 10 Pg. 1081-90 (Oct 2006) ISSN: 1860-7179 [Print] Germany
• PMID: 16921580 (Publication Type: Journal Article)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Nucleoside-Phosphate Kinase
• dTMP kinase
• Thymidine

Topics

• Binding Sites
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Microbial Sensitivity Tests
• Models, Molecular
• Molecular Conformation
• Mycobacterium bovis (drug effects)
• Mycobacterium tuberculosis (enzymology)
• Nucleoside-Phosphate Kinase (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Thymidine (analogs & derivatives, chemical synthesis, pharmacology)