TY - JOUR
T1 - Polygala tenuifolia-Acori tatarinowii herbal pair as an inspiration for substituted cinnamic α-asaronol esters
T2 - Design, synthesis, anticonvulsant activity, and inhibition of lactate dehydrogenase study
AU - Bai, Yajun
AU - He, Xirui
AU - Bai, Yujun
AU - Sun, Ying
AU - Zhao, Zefeng
AU - Chen, Xufei
AU - Li, Bin
AU - Xie, Jing
AU - Li, Yang
AU - Jia, Pu
AU - Meng, Xue
AU - Zhao, Ye
AU - Ding, Yanrui
AU - Xiao, Chaoni
AU - Wang, Shixiang
AU - Yu, Jie
AU - Liao, Sha
AU - Zhang, Yajun
AU - Zhu, Zhiling
AU - Zhang, Qiang
AU - Zhao, Yuhui
AU - Qin, Fanggang
AU - Zhang, Yi
AU - Wei, Xiaoyang
AU - Zeng, Min
AU - Liang, Jing
AU - Cuan, Ye
AU - Shan, Guangzhi
AU - Fan, Tai Ping
AU - Wu, Biao
AU - Zheng, Xiaohui
N1 - Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Anticonvulsant compounds
KW - Combination of traditional Chinese medicine molecular chemistry
KW - Lactate dehydrogenase inhibitor
KW - Polygala tenuifolia-Acori tatarinowii herbal pair
UR - http://www.scopus.com/inward/record.url?scp=85072217857&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2019.111650
DO - 10.1016/j.ejmech.2019.111650
M3 - Article
C2 - 31539780
AN - SCOPUS:85072217857
SN - 0223-5234
VL - 183
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 111650
ER -