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

ChemMedChem. 2006 Oct;1(10):1081-90. doi: 10.1002/cmdc.200600028.

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.

MeSH terms

  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / 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
  • Thymidine / chemical synthesis*
  • Thymidine / pharmacology*

Substances

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