Design and synthesis of novel 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity

Eur J Med Chem. 2014 Jun 10:80:167-74. doi: 10.1016/j.ejmech.2014.04.045. Epub 2014 Apr 15.

Abstract

A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC50 of 0.31 μM showing promising degree of anti-inflammatory activity in the carrageenan-induced rat paw edema model with ED50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid-induced writhes comparable to that of aspirin and gastro-sparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-2 than COX-1.

Keywords: 1,3,4-Oxadiazole; Analgesic; Anti-inflammatory; COX-2; Molecular docking analysis; Pyrazole.

MeSH terms

  • Analgesics / adverse effects
  • Analgesics / chemical synthesis
  • Analgesics / metabolism
  • Analgesics / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Chemistry Techniques, Synthetic
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / chemistry
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / adverse effects
  • Cyclooxygenase 2 Inhibitors / chemical synthesis*
  • Cyclooxygenase 2 Inhibitors / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation
  • Oxadiazoles / adverse effects
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / metabolism
  • Oxadiazoles / pharmacology*
  • Protein Conformation
  • Rats
  • Stomach Ulcer / chemically induced
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Oxadiazoles
  • 1,3,4-oxadiazole
  • Cyclooxygenase 1
  • Cyclooxygenase 2