化学
白藜芦醇
塞来昔布
药理学
体内
罗非昔布
酰胺
毒性
对接(动物)
选择性
水肿
消炎药
生物化学
立体化学
环氧合酶
酶
医学
催化作用
内科学
生物
有机化学
生物技术
护理部
作者
Xin Min,Haoyu Wu,Yuan Du,Sheng Liu,Feng Zhao,Xiaofeng Mou
标识
DOI:10.1016/j.cbi.2023.110522
摘要
Selective COX-2 inhibitors have been considered to be reliable alternatives to tNSAIDs, but most of them were withdrawn from the market due to their risk of heart attack and stroke. Therefore, it is urgent to develop a new type of selective COX-2 inhibitor with high efficiency and low toxicity. Inspired by the cardiovascular protection, and anti-inflammatory activity of resveratrol, we synthesized 38 resveratrol amide derivatives and evaluated their COX-1/COX-2 inhibitory activities. Compounds 8a, 6a, 8c and 13c showed important inhibitory activity against COX-2 (IC50 = 0.42–2.54 μM) with definite selectivity (SI = 48–83). Molecular docking study demonstrated that these compounds partially entered the 2°-pocket of the COX-2 active site and interacted with the amino acid residues responsible for the COX-2 selectivity, which was in a similar orientation and binding interactions to rofecoxib. Further anti-inflammatory activity evaluation in vivo of these active compounds revealed that compound 8a showed no gastric ulcer toxicity, and displayed evident anti-inflammatory effect (45.95% inhibition of edema) with three oral doses of 50 mg/kg, which is worthy of further study. Moreover, compounds 6a and 8c also exhibited superior gastric safety profiles compared to the reference drugs celecoxib and indomethacin.
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