Molvi Khurshid I, Vasu Kamala K, Yerande Swapnil G, Sudarsanam Vasudevan, Haque Navedul
School of Pharmacy, Faculty of Medical Sciences, Jimma University, P.O. Box 378, Jimma, Oromia, Ethiopia.
Eur J Med Chem. 2007 Aug;42(8):1049-58. doi: 10.1016/j.ejmech.2007.01.007. Epub 2007 Jan 24.
A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.
一系列新型四取代噻吩（4a - 4i、5a - 5i和6a - 6f）已被合成为新型抗炎剂，并在角叉菜胶诱导的大鼠后爪水肿模型中，以10、20和40mg/kg体重的剂量评估了它们的抗炎活性。在酯类系列中，最佳化合物4c在10mg/kg时对发炎爪子的保护率为71%，20mg/kg时为72%，40mg/kg时为76%；而在酸类系列中，5a在10mg/kg时对发炎爪子的保护率为79%，20mg/kg时为80%，40mg/kg时为70%，5c在10mg/kg时为72%，20mg/kg时为75%，40mg/kg时为69%。在肟类系列6a - 6f中，与酸类和酯类系列相比，候选物的抗炎活性较差。基于对目标化合物的构效关系研究发现，在R(2)位存在OCH(3)以及在R(1)位存在H、OCH(3)是四取代噻吩酯类和酸类系列中引发相当抗炎活性的要求之一。在乙酸诱导的扭体反应模型中，以10mg/kg剂量研究了化合物4a - 4i、5a - 5i的镇痛活性。在酯类系列中，化合物4e表现出最大保护率60%，而4a、4b和4i分别表现出55%、45%和43%的保护率。结果表明，四取代噻吩酯类系列中R(1)位存在H、Cl以及R(2)位存在OCH(3)、CH(3)可增强其镇痛活性。与标准药物布洛芬相比，酸类系列5a - 5i的候选物表现出较差的镇痛活性。对化合物4a - 4i、5a - 5i进行了体外抗氧化一氧化氮自由基清除试验评估。在酯类系列中，4a表现出最大的体外一氧化氮自由基清除活性，IC(50)值为30.08μg/ml，而在酸类系列中，5a的IC(50)值为25.20μg/ml。结果表明，R(1)=H、R(2)=OCH(3)以及R(1)=R(2)=OCH(3)的存在增强了四取代噻吩酸类系列中的一氧化氮自由基清除性能。
