Identification and development of 2-methylimidazo[1,2-a]pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors

Bioorg Med Chem. 2014 Aug 1;22(15):4223-32. doi: 10.1016/j.bmc.2014.05.038. Epub 2014 May 23.

Abstract

In the present study, we used crystal structure of mycobacterial pantothenate synthetase (PS) bound with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl) acetic acid inhibitor for virtual screening of antitubercular compound database to identify new scaffolds. One of the identified lead was modified synthetically to obtain thirty novel analogues. These synthesized compounds were evaluated for Mycobacterium tuberculosis (MTB) PS inhibition study, in vitro antimycobacterial activities and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, N'-(1-naphthoyl)-2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (5b) was found to be the most active compound with IC₅₀ of 1.90 ± 0.12 μM against MTB PS, MIC of 4.53 μM against MTB with no cytotoxicity at 50 μM. The binding affinity of the most potent inhibitor 5b was further confirmed biophysically through differential scanning fluorimetry.

Keywords: 2-Methylimidazo[1,2-a]pyridine-3-carbohydrazide; Cytotoxicity; Pantothenate synthetase; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Catalytic Domain
  • Cell Line
  • Cell Survival / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Dynamics Simulation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology*
  • Peptide Synthases / antagonists & inhibitors*
  • Peptide Synthases / metabolism
  • Pyridines / chemistry
  • Structure-Activity Relationship

Substances

  • Amides
  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Pyridines
  • Peptide Synthases
  • pantothenate synthetase
  • imidazo(1,2-a)pyridine