Design,Synthesis and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents  

作　　者：QUAN Jishun ZHANG Dongping ZHANG Zhuo WANG Jian MA Chao CHENG Maosheng 

机构地区：[1]Key Laboratory of Structure-based Drug Design&Discovery of Ministry of Education,School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang,110016,P.R.China

出　　处：《Chemical Research in Chinese Universities》2021年第3期647-654,共8页高等学校化学研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(No.21977074);the Science and Technology Projects from the Educational Department of Liaoning Province,China(No.2019LQN02).

摘　　要：A series of pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione derivatives was designed and synthesized,and their neuroprotective activity against SH-SY5Y cell injury induced by N-methyl-D-aspartic acid(NMDA)was evaluated.All the compounds showed significant neuroprotective effects,especially B16,which showed excellent performance and better activity than the positive control ifenprodil(B16:56.2%±0.6%;ifenprodil:41.0%±2.7%).Further investigation indicated that B16 could attenuate the Ca^(2+)influx induced by NMDA in SH-SY5Y cells and Western blotting also showed that B16 could attenuate the NR2B upregulation in SH-SY5Y cells induced by NMDA.The molecular docking results showed that compound B16 fitted in the binding pocket of NR2B-NMDAR well and could interact with binding sites of compounds 1 and 2 simultaneously.The ADME/Tox prediction results suggested that compound B16 had good blood-brain barrier(BBB)permeability and the zero alert of Pan Assay Interference Structures(PAINS)indicated that B16 could not elicit false-positive activities.These results strongly suggest that B16 is a promising and effective candidate neuroprotective compound,and that NR2B-NMDAR is a potential target of B16.

关 键 词：Neuroprotective activity Ca^(2+)influx Western blotting NR2B-NMDA receptor Molecular docking 

分 类 号：TQ460.1[化学工程—制药化工]