Molvi Khurshid I, Sudarsanam Vasudevan, M Patel Madhubhai, Haque Navedul
School of Pharmacy, Faculty of Medical Sciences, Jimma University, Jimma, Ethiopia.
J Enzyme Inhib Med Chem. 2008 Dec;23(6):819-28. doi: 10.1080/14756360701608692.
A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL were performed using standard drug ascorbic acid.
设计了一系列新的四取代噻吩类似物（4a - 4f、5a - 5f和8a - 8i），它们融合了COX - 1（如在非甾体抗炎芬那酸类药物中）、5 - 脂氧合酶（5 - LOX）和p38丝裂原活化蛋白激酶（p38 MAP激酶）抑制剂的药效基团特征。通过芳基/芳酰基异硫氰酸酯与烯胺（2）的亲核加成反应合成了该系列化合物，得到加成产物1 -（α - 甲氧羰基 - β - 氨基硫代巴豆酰基）- 芳基/芳酰基胺（3/7）；其与取代苯甲酰溴反应得到目标四取代噻吩酯（4a - 4f / 8a - 8i）。四取代噻吩酯（4a - 4f）在室温下于甲醇中用一当量氢氧化钾溶液水解得到相应的酸（5a - 5f）。使用标准药物甲芬那酸和布洛芬，在角叉菜胶诱导的大鼠后爪水肿模型中，以10、20和40 mg/kg体重的剂量对所有目标化合物的抗炎活性进行了评估。选择对发炎爪子有合理保护作用、具有良好或中等相当抗炎活性的化合物（4c、4e、4f、5f、8a - 8i），在白化小鼠中以10 mg/kg剂量使用标准药物布洛芬通过乙酸诱导的扭体反应试验研究其镇痛活性，并且为了探究其抗炎活性的可能机制，使用标准药物抗坏血酸在5、10、15、20、25、30和35 μg/mL浓度下进行体外抗氧化一氧化氮自由基清除试验。
