Functionalized 3-amino-imidazo[1,2-a]pyridines: a novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4790-3. doi: 10.1016/j.bmcl.2009.06.045. Epub 2009 Jun 14.

Abstract

3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC(50)=0.38+/-0.02 microM). This compound was significantly more potent than the known inhibitors, l-methionine-SR-sulfoximine and phosphinothricin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Glutamate-Ammonia Ligase / antagonists & inhibitors*
  • Glutamate-Ammonia Ligase / metabolism
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Mycobacterium tuberculosis / enzymology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Structure-Activity Relationship

Substances

  • 3-amino-imidazo(1,2-a)pyridine
  • Antitubercular Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Glutamate-Ammonia Ligase