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

doi:10.1007/s40242-020-0283-z

Abstract

Abstract: Aseries 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 Ca²⁺ 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.

Key words: Neuroprotective activity, Ca²⁺ influx, Western blotting, NR2B-NMDA receptor, Molecular docking

QUAN Jishun, ZHANG Dongping, ZHANG Zhuo, WANG Jian, MA Chao, CHENG Maosheng. Design, Synthesis and Biological Evaluation of Pyrrolo[2,1-c] [1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents[J]. Chemical Research in Chinese Universities, 2021, 37(3): 647-654.

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