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

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Chemical Research in Chinese Universities Aims and scope

Abstract

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 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.

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Acknowledgements

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

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Authors and Affiliations

  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

    Jishun Quan, Dongping Zhang, Zhuo Zhang, Jian Wang, Chao Ma & Maosheng Cheng

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  1. Jishun Quan
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  2. Dongping Zhang
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  3. Zhuo Zhang
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  4. Jian Wang
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  5. Chao Ma
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  6. Maosheng Cheng
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Correspondence to Chao Ma or Maosheng Cheng.

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Quan, J., Zhang, D., Zhang, Z. et al. Design, Synthesis and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents. Chem. Res. Chin. Univ. 37, 647–654 (2021). https://doi.org/10.1007/s40242-020-0283-z

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  • DOI: https://doi.org/10.1007/s40242-020-0283-z

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