n -取代尼培他胺衍生物多功能癫痫药物的设计、合成及生物学评价

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-10 DOI:10.1016/j.ejmech.2025.117613

Wei Li, Lijun Hong, Linrui Li, Yu Yuan, Yi Ding, Jiang Zhu, Chao Wang, Zhongcheng Cao, Xin Tian

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引用次数: 0

摘要

为了发现新的多功能抗癫痫药物，我们将尼培他胺与水杨醛、丹皮酚、香兰素和肉桂醛杂交，合成了一系列n取代尼培他胺衍生物。生物筛选表明，化合物11c对ABTS（2,2′- azinobis -（3-乙基苯并噻唑-6-磺酸））自由基（清除IC50: 92.0 μM）、DPPH（1,1-二苯基-2-picrylhydrazyl）自由基（清除IC50: 70.9 μM）和超氧阴离子自由基（抑制率：48.4%）具有显著的清除活性。此外，电生理结果表明，化合物11c对异常放电有较强的抑制作用。此外，化合物11c在细胞水平上显示出减轻h2o2诱导的氧化损伤和lps诱导的神经炎症的能力。此外，化合物11c能穿越血脑屏障，有效缓解戊四唑和匹罗卡品所致的癫痫症状，减轻亚硝酸钠对小鼠的氧化损伤。因此，化合物11c对癫痫具有对症治疗和改善疾病的特性。这些结果表明，化合物11c作为抗癫痫药物具有很大的开发潜力。

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Design, synthesis and biological evaluation of N-substituted nipecotamide derivatives as multifunctional agents for epilepsy treatment

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Design, synthesis and biological evaluation of N-substituted nipecotamide derivatives as multifunctional agents for epilepsy treatment

To discover novel multi-functional antiepileptic agents, nipecotamide was hybridized with salicylaldehyde, paeonol, vanillin and cinnamaldehyde to generate a series of N-substituted nipecotamide derivatives. Biological screening revealed that compound 11c exhibited remarkable scavenging activities against ABTS (2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) ) radical (scavenging IC₅₀: 92.0 μM), DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical (scavenging IC₅₀: 70.9 μM), and superoxide anion radical (inhibition percentage: 48.4%). Additionally, electrophysiological results showed that compound 11c demonstrated potent inhibitory effects on abnormal electrical discharges. Furthermore, compound 11c displayed the capacity to relieve H₂O₂-induced oxidative damage and LPS-induced neuroinflammation at the cellular level. Besides, compound 11c could cross the blood-brain barrier, alleviate the symptoms of epilepsy induced by pentylenetetrazole and pilocarpine effectively, and mitigate oxidative damage caused by sodium nitrite in mice. Therefore, compound 11c possesses symptomatic-treatment and disease-modification properties for epilepsy. These results highlighted that compound 11c was a highly promising candidate for further development as an antiepileptic agent.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.