Structural exploration, synthesis and pharmacological evaluation of novel 5-benzylidenethiazolidine-2,4-dione derivatives as iNOS inhibitors against inflammatory diseases

Eur J Med Chem. 2015 Mar 6:92:178-90. doi: 10.1016/j.ejmech.2014.12.036. Epub 2014 Dec 26.

Abstract

In our previous work, 3I inhibited the LPS-induced iNOS activity and NO production in RAW 264.7 cells and improved joint inflammation and cartilage destruction in inflammatory model. In this study, we synthesized 59 derivatives and bioisosteres on the basis of 3I by Knoevenagel condensation and biologically evaluated for the study of structure-activity relationship (SAR). We found that 7-44 suppressed the iNOS activity (IC50 25.2 μM) and LPS-induced NO production (IC50 45.6 μM) in RAW 264.7 cells. As for the SAR study, the dimethoxylphenyl group of 7-44 was potential for a further modification. At a dose of 10 mg/kg, oral administration of 7-44 possessed protective properties in both carrageenan-induced paw edema of male ICR mice and adjuvant-induced arthritis of Lewis female rats. Although the activity of 7-44 was slightly inferior, the PK profiles of 7-44 were superior to those of 3I.

Keywords: 5-Benzylidenethiazolidine-2,4-dione; Inducible nitric oxide synthase; Inflammation; Nitric oxide; Paw edema.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzylidene Compounds / chemical synthesis
  • Benzylidene Compounds / chemistry
  • Benzylidene Compounds / pharmacology*
  • Carrageenan
  • Cell Line
  • Dose-Response Relationship, Drug
  • Edema / chemically induced
  • Edema / drug therapy
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Inflammation / drug therapy*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Structure
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*

Substances

  • 5-benzylidene thiazolidine-2,4-dione
  • Benzylidene Compounds
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Thiazolidinediones
  • Nitric Oxide
  • Carrageenan
  • Nitric Oxide Synthase Type II