Synthesis and Biological Evaluation of Novel 5-Benzylidenethiazolidine-2,4-dione Derivatives for the Treatment of Inflammatory Diseases
Synthesis and Biological Evaluation of Novel 5-Benzylidenethiazolidine-2,4-dione Derivatives for the Treatment of Inflammatory Diseases
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DOI：
10.1021/jm1011534
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发表时间：
2011-04-14
影响因子：
7.3
通讯作者：
Chen, Lijuan
中科院分区：
文献类型：
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作者：
Ma, Liang;Xie, Caifeng;Chen, Lijuan
合成了 22 种基于噻唑烷-2,4-二酮部分的化合物，并评估了其对一氧化氮 (NO) 产生、诱导型一氧化氮合酶 (iNOS) 活性和前列腺素 E-2 (PEG(2)) 产生的抑制效力。 (Z)-N-(3-氯苯基)-2-(4-((2,4-二氧噻唑烷-5-亚基)甲基)苯氧基)乙酰胺(3I)，优于市售抗炎药吲哚美辛，显着抑制iNOS活性(IC50 = 8.66 mu M)、iNOS介导的NO和环氧烯酶 脂多糖 (LPS) 诱导的 (COX)-2 衍生的 PGE(2) 产生（IC50 分别为 4.16 和 23.55 muM）。原始 264.7 细胞。对接研究表明，3I 完美对接至小鼠 iNOS 活性位点，并通过 Western blot 分析抑制了 iNOS 蛋白的表达。在剂量为 50 mg/kg 时，口服 3I 对角叉菜胶诱导的足肿胀和佐剂诱导的关节炎大鼠模型均具有保护作用。
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 (IC50 = 8.66 mu M), iNOS-mediated NO, and cyclooxnenase (COX)-2-derived PGE(2) production (IC50 = 4.16 and 23.55 mu M, 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.