Design, synthesis, and structure-activity relationships of pyrazole derivatives as potential FabH inhibitors

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4657-60. doi: 10.1016/j.bmcl.2010.05.105. Epub 2010 Jun 8.

Abstract

Fatty acid biosynthesis is essential for bacterial survival. FabH, beta-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (13) were potent inhibitors of E. coli FabH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Computer Simulation
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship

Substances

  • 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Pyrazoles
  • pyrazole
  • 3-ketoacyl-acyl carrier protein synthase III
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase