Khatri Chetan K, Indalkar Krishna S, Patil Chandragouda R, Goyal Sameer N, Chaturbhuj Ganesh U
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, Maharashtra, India.
Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist-Dhule 425405, Maharashtra, India.
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1721-1726. doi: 10.1016/j.bmcl.2017.02.076. Epub 2017 Mar 8.
A series of 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene derivatives were synthesized and evaluated for in vitro COX inhibitory potential. Within the series, compounds 4a, 4j, 4k, and 4q were identified as potential and selective COX-2 inhibitors with COX-2 IC in 0.31-1.40µM range; COX-2 selectivity index (SI)=48.8-183.8 range and they showed percent PGE-2 inhibitory activity in the range of 25.4-46.9. Further, compounds 4a, 4j, 4k and 4q displayed potent anti-inflammatory activity with percentage rise in paw volume ranging from 21.1-30.5 at 180min, while celecoxib demonstrated 19.6 percentage rise at the same dose at 180min in carrageenan-induced rat paw edema assay. Cell viability via MTT assay showed no cytotoxicity up to 80µM concentrations. Molecular docking study of potent compounds in the series showed Gscore comparable to celecoxib with similar binding orientation for the COX-2 active site which also corroborates the observed in vitro COX-2 inhibition.
合成了一系列2-苯基-4,5,6,7-四氢[b]苯并噻吩衍生物，并对其体外COX抑制潜力进行了评估。在该系列化合物中，化合物4a、4j、4k和4q被鉴定为潜在的选择性COX-2抑制剂，其COX-2 IC50在0.31-1.40µM范围内；COX-2选择性指数（SI）在48.8-183.8范围内，它们显示出25.4-46.9范围内的PGE-2抑制活性百分比。此外，在角叉菜胶诱导的大鼠足肿胀试验中，化合物4a、4j、4k和4q在180分钟时显示出强大的抗炎活性，足体积增加百分比在21.1-30.5之间，而塞来昔布在相同剂量下在180分钟时显示出19.6的增加百分比。通过MTT试验进行的细胞活力测定表明，在高达80µM的浓度下没有细胞毒性。该系列中活性化合物的分子对接研究表明，其Gscore与塞来昔布相当，对COX-2活性位点具有相似的结合方向，这也证实了观察到的体外COX-2抑制作用。
