Synthesis, cyclooxygenase inhibitory effects, and molecular modeling study of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and -2-alkylsulfonyl-1H-imidazole derivatives

Bioorg Med Chem. 2013 Apr 15;21(8):2355-2362. doi: 10.1016/j.bmc.2013.01.058. Epub 2013 Feb 8.

Abstract

A series of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and 2-alkylsulfonyl-1H-imidazole derivatives were synthesized. All compounds were tested in human blood assay to determine COX-1 and COX-2 inhibitory potency and selectivity. Among the synthesized compounds, 2-alkylthio series were more potent and selective than 2-sulfonylalkyl derivatives. In molecular modeling, interaction of 2-sulfonylalkyl moiety with Arg120 in COX-1 and an extra hydrogen bond with Tyr341 in COX-2 increased the residence time of ligands in the active site in 2-sulfonylalkyl and 2-alkylthio analogs, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclooxygenase 1 / blood
  • Cyclooxygenase 2 / blood
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Cyclooxygenase Inhibitors
  • Imidazoles
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human