Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4-dione derivatives for the treatment of inflammatory diseases.

Abstract

Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E(2) (PEG(2)). (Z)-N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC(50) = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE(2) production (IC(50) = 4.16 and 23.55 μM, respectively) on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Docking study revealed that 3I was perfectly docking into the active site of murine iNOS and suppressed the expression of iNOS protein as evidenced by Western blot analysis. At the dose of 50 mg/kg, oral administration of 3I possessed protective properties in both carrageenan-induced paw edema and adjuvant-induced arthritis rat models.

• Authors: Liang Ma, Caifeng Xie, Yinghua Ma, Juan Liu, Mingli Xiang, Xia Ye, Hao Zheng, Zhizhi Chen, Qinyuan Xu, Tao Chen, Jinying Chen, Jincheng Yang, Neng Qiu, Guangcheng Wang, Xiaolin Liang, Aihua Peng, Shengyong Yang, Yuquan Wei, Lijuan Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 7 Pg. 2060-8 (Apr 14 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21381754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Benzylidene Compounds
• Lipopolysaccharides
• Thiazolidinediones
• Nitric Oxide
• Carrageenan
• 2,4-thiazolidinedione
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Arthritis, Experimental (drug therapy)
• Benzylidene Compounds (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Carrageenan (pharmacology)
• Cell Line
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (biosynthesis)
• Dose-Response Relationship, Drug
• Edema (chemically induced, drug therapy)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Inflammation (drug therapy, enzymology, metabolism)
• Inhibitory Concentration 50
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Models, Molecular
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type II (chemistry, metabolism)
• Protein Conformation
• Rats
• Thiazolidinediones (chemical synthesis, pharmacology, therapeutic use, toxicity)