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

• Published in: European journal of medicinal chemistry 2019-12, Vol.183, p.111650, Article 111650
• Main Authors: Bai, Yajun, He, Xirui, Bai, Yujun, Sun, Ying, Zhao, Zefeng, Chen, Xufei, Li, Bin, Xie, Jing, Li, Yang, Jia, Pu, Meng, Xue, Zhao, Ye, Ding, Yanrui, Xiao, Chaoni, Wang, Shixiang, Yu, Jie, Liao, Sha, Zhang, Yajun, Zhu, Zhiling, Zhang, Qiang, Zhao, Yuhui, Qin, Fanggang, Zhang, Yi, Wei, Xiaoyang, Zeng, Min, Liang, Jing, Cuan, Ye, Shan, Guangzhi, Fan, Tai-Ping, Wu, Biao, Zheng, Xiaohui
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Anisoles - chemistry; Anisoles - pharmacology; Anticonvulsant compounds; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Carbamazepine - chemistry; Carbamazepine - pharmacology; Cinnamates - chemistry; Cinnamates - pharmacology; Combination of traditional Chinese medicine molecular chemistry; Dioxolanes - chemistry; Dioxolanes - pharmacology; Drug Design; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Esters - chemistry; Esters - pharmacology; Humans; L-Lactate Dehydrogenase - antagonists & inhibitors; Lactate dehydrogenase inhibitor; Medicine, Chinese Traditional; Mice; Molecular Structure; Neuralgia - prevention & control; Polygala - chemistry; Polygala tenuifolia-Acori tatarinowii herbal pair; Receptors, GABA-A - metabolism; Structure-Activity Relationship; Valproic Acid - chemistry; Valproic Acid - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111650

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. Chart 1. Compounds with subunit of propenylic phenylpropene. [Display omitted] •Substituted cinnamic α-asaronol esters and amides were synthesized and screened for anticonvulsant and LDH inhibitory effect.•Compounds 68-70 and 75 exhibited higher antiepileptic activity and lower neurotoxicity than stiripentol.•The inhibition of LDH1 and LDH5 by compound 68-70 were noncompetitive and were at least four times higher than stiripentol.•Compound 70 could allosterically regulate human α1β2γ2 GABAA receptor with EC50 46.3 ± 7.3 μM.•68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies.