Polygala tenuifolia-Acori tatarinowii herbal pair as an inspiration for substituted cinnamic α-asaronol esters: Design, synthesis, anticonvulsant activity, and inhibition of lactate dehydrogenase study

Yajun Bai, Xirui He, Yujun Bai, Ying Sun, Zefeng Zhao, Xufei Chen, Bin Li, Jing Xie, Yang Li, Pu Jia, Xue Meng, Ye Zhao, Yanrui Ding, Chaoni Xiao, Shixiang Wang, Jie Yu, Sha Liao, Yajun Zhang, Zhiling Zhu, Qiang ZhangYuhui Zhao, Fanggang Qin, Yi Zhang, Xiaoyang Wei, Min Zeng, Jing Liang, Ye Cuan, Guangzhi Shan, Tai Ping Fan, Biao Wu, Xiaohui Zheng*

*此作品的通讯作者

科研成果: 期刊稿件文章同行评审

21 引用 (Scopus)

摘要

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68–70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68–70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1β2γ2 GABAA receptors (EC50 46.3 ± 7.3 μM). Thus, 68–70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.

源语言英语
文章编号111650
期刊European Journal of Medicinal Chemistry
183
DOI
出版状态已出版 - 1 12月 2019
已对外发布

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