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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.

Abstract：

: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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Bai Y,He X,Bai Y,Sun Y,Zhao Z,Chen X,Li B,Xie J,Li Y,Jia P,Meng X,Zhao Y,Ding Y,Xiao C,Wang S,Yu J,Liao S,Zhang Y,Zhu Z,Zhang Q,Zhao Y,Qin F,Zhang Y,Wei X,Zeng M,Liang J,Cuan Y,Shan G,Fan TP,Wu B

doi

10.1016/j.ejmech.2019.111650

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

111650

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30790-1

journal_volume

183

pub_type

杂志文章

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