Chiral 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: evaluation of COX-2 selectivity and modelling

Bioorg Med Chem. 2003 Mar 20;11(6):999-1006. doi: 10.1016/s0968-0896(02)00518-7.

Abstract

Anti-inflammatory/analgesic 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] 1, obtained as racemic mixtures (a) and mesoforms (b), have two equivalent stereogenic centres (C-2 and C-2') and exist as RR, SS and RS isomers. The enantioseparation of 1a provided the single enantiomers that displayed different in vitro cyclooxygenase-1/cyclooxygenase-2 selectivity ratios. In particular the dextrorotatory compound is a highly selective COX-2 inhibitor and the levorotatory one is moderately selective. Instead, RS-meso isomer (1b) exhibited similar levels of inhibitory activity on both COX isozymes. The diastereo- and enantioselectivity has been explained by molecular modelling of RR, SS and RS compounds into COX-1 and COX-2 binding sites. Theoretical results indicated SS>RS>RR affinity order towards COX-2 isoenzyme, in agreement with in vitro and previous in vivo pharmacological results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Binding Sites
  • Chemical Phenomena
  • Chemistry, Physical
  • Crystallography, X-Ray
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Membrane Proteins
  • Models, Molecular
  • Monocytes / drug effects
  • Prostaglandin-Endoperoxide Synthases / chemistry
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Protein Conformation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology*
  • Thromboxane B2 / antagonists & inhibitors

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • Thiazoles
  • Thromboxane B2
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases