Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

Bioorg Med Chem Lett. 2014 Oct 1;24(19):4638-4642. doi: 10.1016/j.bmcl.2014.08.050. Epub 2014 Aug 29.

Abstract

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a-d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50's in 1.79-4.35μM range; COX-2 selectivity index (SI)=6.8-16.7 range). Compound 3b emerged as most potent (COX-2 IC50=1.79μM; COX-1 IC50 >30μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5h) in comparison to celecoxib (51.44% inhibition of edema at 5h) in carrageenan-induced rat paw edema assay. Structure-activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.

Keywords: 3-Methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones; Anti-inflammatory; Cyclooxygenase-2; Molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Carrageenan
  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / chemical synthesis
  • Cyclooxygenase 2 Inhibitors / chemistry
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Edema / chemically induced
  • Edema / drug therapy*
  • Molecular Docking Simulation*
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Rats
  • Sheep
  • Structure-Activity Relationship

Substances

  • 3-methyl-1-(4-(trifluoromethyl)phenylchromeno(4,3-c)pyrazol-4(1H)-one
  • Anti-Inflammatory Agents, Non-Steroidal
  • Coumarins
  • Cyclooxygenase 2 Inhibitors
  • Pyrazoles
  • Carrageenan
  • Cyclooxygenase 2