Nanomolar inhibitors of Mycobacterium tuberculosis glutamine synthetase 1: synthesis, biological evaluation and X-ray crystallographic studies

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1455-9. doi: 10.1016/j.bmcl.2015.02.035. Epub 2015 Feb 23.

Abstract

A series of imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones that potently inhibit M. tuberculosis glutamine synthetase (GlnA1) has been identified by high throughput screening. Exploration of this series was performed owing to a short chemistry program. Despite possibly nanomolar inhibitions, none of these compounds was active on whole cell Mtb, suggesting that GlnA1 may not be a suitable target to find new anti-tubercular drugs.

Keywords: GlnA1 inhibitors; Glutamine synthetase; High throughput screening; Tuberculosis; X-ray crystallography.

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glutamate-Ammonia Ligase / antagonists & inhibitors*
  • Glutamate-Ammonia Ligase / metabolism
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • High-Throughput Screening Assays
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*

Substances

  • Antitubercular Agents
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 4 or More Rings
  • Imidazoles
  • Pyrazines
  • glutamine synthetase I
  • Glutamate-Ammonia Ligase