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

高等学校化学研究 ›› 2021, Vol. 37 ›› Issue (3): 647-654.doi: 10.1007/s40242-020-0283-z

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

QUAN Jishun, ZHANG Dongping, ZHANG Zhuo, WANG Jian, MA Chao, CHENG Maosheng

Key Laboratory of Structure-based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China

收稿日期:2020-09-11 修回日期:2020-10-21 出版日期:2021-06-01 发布日期:2020-11-04
通讯作者: MA Chao, CHENG Maosheng E-mail:machao@syphu.edu.cn;mscheng@syphu.edu.cn
基金资助:
This work was supported by the National Natural Science Foundation of China(No.21977074) and the Science and Technology Project from the Educational Department of Liaoning Province, China(No.2019LQN02).

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

QUAN Jishun, ZHANG Dongping, ZHANG Zhuo, WANG Jian, MA Chao, CHENG Maosheng

Key Laboratory of Structure-based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China

Received:2020-09-11 Revised:2020-10-21 Online:2021-06-01 Published:2020-11-04
Contact: MA Chao, CHENG Maosheng E-mail:machao@syphu.edu.cn;mscheng@syphu.edu.cn
Supported by:
This work was supported by the National Natural Science Foundation of China(No.21977074) and the Science and Technology Project from the Educational Department of Liaoning Province, China(No.2019LQN02).

摘要/Abstract

摘要： 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.

关键词: Neuroprotective activity, Ca²⁺ influx, Western blotting, NR2B-NMDA receptor, Molecular docking

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]. 高等学校化学研究, 2021, 37(3): 647-654.

参考文献 24

[1]	Buemi M. R., De Luca L., Ferro S., Russo E., De Sarro G., Gitto R., Bioorg. Med. Chem., 2016, 24, 1513
[2]	Dey S., Schepmann D., Wunsch B., Bioorg. Med. Chem. Lett., 2016, 26, 889
[3]	Gitto R., De Luca L., Ferro S., Buemi M. R., Russo E., De Sarro G., Costa L., Ciranna L., Prezzavento O., Arena E., Ronsisvalle S., Bruno, G., Chimirri A., J. Med. Chem., 2011, 54, 8702
[4]	Parsons C. G., Danysz W., Quack G., Drug News Perspect, 1998, 11, 523
[5]	Tewes B., Frehland B., Schepmann D., Schmidtke K. U., Winckler T., Wunsch B., Bioorg. Med. Chem., 2010, 18, 8005
[6]	Cadinu D., Grayson B., Podda G., Harte M. K., Doostdar N., Neill J. C., Neuropharmacology, 2018, 142, 41
[7]	Potschka H., Loscher W., Wlaz P., Behl B., Hofmann H. P., Treiber H. J., Szabo L., Br. J. Pharmacol., 1998, 125, 1258
[8]	Glynn-Servedio B. E., Ranola T. S., Consult Pharm., 2017, 32, 511
[9]	Shi T., Hao J. X., Wiesenfeld-Hallin Z., Xu X. J., Scand. J. Pain., 2018, 18, 687
[10]	Milnerwood A. J., Gladding C. M., Pouladi M. A., Kaufman A. M., Hines R. M., Boyd J. D., Ko R. W., Vasuta O. C., Graham R. K., Hayden M. R., Murphy T. H., Raymond L. A., Neuron, 2010, 65, 178
[11]	Krausova B., Slavikova B., Nekardova M., Hubalkova P., Vyklicky V., Chodounska H., Vyklicky L., Kudova E., Journal of Medicinal Chemistry, 2018, 61, 4505
[12]	von Engelhardt J., Coserea I., Pawlak V., Fuchs E. C., Kohr G., Seeburg P. H., Monyer H., Neuropharmacology, 2007, 53, 10
[13]	Loftis J. M., Janowsky A., Pharmacol. Ther., 2003, 97, 55
[14]	Furukawa H., Singh S. K., Mancusso R., Gouaux E., Nature, 2005, 438, 185
[15]	Williams K., Curr. Drug Targets, 2001, 2, 285
[16]	Chenard B. L., Bordner J., Butler T. W., Chambers L. K., Collins M. A., De Costa D. L., Ducat M. F., Dumont M. L., Fox C. B., Journal of Medicinal Chemistry, 1995, 38, 3138
[17]	Fischer G., Mutel V., Trube G., Malherbe P., Kew J. N., Mohacsi E., Heitz M. P., Kemp J. A., The Journal of Pharmacology and Experimental Therapeutics, 1997, 283, 1285
[18]	Stroebel D., Buhl D. L., Knafels J. D., Chanda P. K., Green M., Sciabola S., Mony L., Paoletti P., Pandit J., Mol. Pharmacol., 2016, 89, 541
[19]	Koolen H. H., Pral E. M., Alfieri S. C., Marinho J. V., Serain A. F., Hernandez-Tasco A. J., Andreazza N. L., Salvador M. J., Phytochemistry, 2017, 134, 106
[20]	Di Fabio R., Micheli F., Baraldi D., Bertani B., Conti N., Dal Forno G., Feriani A., Donati D., Marchioro C., Messeri T., Missio A., Pasquarello A., Pentassuglia G., Pizzi D. A., Provera S., Quaglia A. M., Sabbatini F. M., Il. Farmaco., 2003, 58, 723
[21]	Ma C., Du K., Zhao Y., Zhang L. K., Hu B. C., Cheng M. S., Bioorg. Med. Chem., 2018, 26, 5151
[22]	Zhang L. K., Zhao Y., Wang J., Yang D. L., Zhao C. W., Wang C. L., Ma C., Cheng M. S., Eur. J. Med. Chem., 2018, 151, 27
[23]	Zhang L. K., Quan J. S., Zhao Y., Yang D. L., Zhao Q. C., Liu P., Cheng M. S., Ma C., Eur. J. Med. Chem., 2019, 182, 111654
[24]	Feng X. Y., Jia W. Q., Liu X., Jing Z., Liu Y. Y., Xu W. R., Cheng X. C., Comput. Biol. Chem., 2019, 78, 178

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

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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