Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors

Bioorg Med Chem. 2013 Jan 1;21(1):257-68. doi: 10.1016/j.bmc.2012.10.018. Epub 2012 Nov 5.

Abstract

We report the synthesis of 5'-modified thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification.

MeSH terms

  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Humans
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Nucleoside-Phosphate Kinase / antagonists & inhibitors*
  • Nucleoside-Phosphate Kinase / metabolism
  • Thymidine / analogs & derivatives*
  • Thymidine / chemistry
  • Thymidine / pharmacology*
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • 5-hydroxymethyl-2'-deoxyuridine
  • Nucleoside-Phosphate Kinase
  • dTMP kinase
  • Thymidine