Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
Eur J Med Chem. 2019 Nov 15;182:111601. doi: 10.1016/j.ejmech.2019.111601. Epub 2019 Aug 9.
The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.
环状烯胺酮部分已被确定为一种新的支架，用于选择性抑制环氧化酶-2，具有抗炎和镇痛活性。设计的环状烯胺酮通过开发新的无催化剂方法方便地合成，并评估其对环氧化酶（COX-1 和 COX-2）的抑制活性。三种化合物 7d、8 和 9 主要抑制 COX-2，其选择性指数分别为 74.09、19.45 和 108.68，并在角叉菜胶诱导的大鼠足肿胀试验中评估其体内抗炎活性。化合物 7d 的抗炎活性与塞来昔布在 12.5mg/kg 剂量下相当。然而，化合物 8 和 9 在 12.5mg/kg 和 25mg/kg 剂量下作为抗炎剂比塞来昔布更有效/同样有效，并且其抗炎活性与双氯芬酸相当。最有效化合物 9 的治疗潜力通过使用各种模型进行体内热和机械痛觉过敏试验进一步评估，这些模型揭示了其镇痛活性。与非选择性 COX 抑制剂吲哚美辛相比，9 的体内非溃疡发生性揭示了其胃肠道安全性。体外抗氧化活性和体内心率和血压实验提供了 9 的心血管安全性概况。分子对接研究合理说明了新发现的抗炎化合物 7d、8 和 9 的 COX-2 选择性。
