Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5149-54. doi: 10.1016/j.bmcl.2011.07.062. Epub 2011 Jul 26.

Abstract

Various 3-nitropropionamides were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among 22 compounds, 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22) was found to be the most active compound in vitro with MICs of 0.16 and 0.04 μM against log- and starved-phase culture of MTB. Compound 22 also showed good enzyme inhibition of MTB ICL with IC(50) of 0.10 ± 0.01 μM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / chemical synthesis
  • Anilides / chemistry
  • Anilides / pharmacology*
  • Catalytic Domain / drug effects
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Isocitrate Lyase / antagonists & inhibitors*
  • Isocitrate Lyase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Nitro Compounds / chemical synthesis
  • Nitro Compounds / chemistry
  • Nitro Compounds / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anilides
  • Enzyme Inhibitors
  • Nitro Compounds
  • Isocitrate Lyase