2. Academic Validation
  3. Design, synthesis and biological evaluation of N-substituted nipecotamide derivatives as multifunctional agents for epilepsy treatment

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

  • Eur J Med Chem. 2025 Apr 10:292:117613. doi: 10.1016/j.ejmech.2025.117613.
Wei Li 1,  Lijun Hong 2,  Linrui Li 2,  Yu Yuan 2,  Yi Ding 2,  Jiang Zhu 3,  Chao Wang 4,  Zhongcheng Cao 5,  Xin Tian 6
Affiliations

Affiliations

  • 1 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China.
  • 2 School of Pharmacy, North Sichuan Medical College, Nanchong, 637000, China.
  • 3 Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong, 637000, China.
  • 4 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. Electronic address: Chwa0028@live.com.
  • 5 School of Pharmacy, North Sichuan Medical College, Nanchong, 637000, China. Electronic address: 18113045205@163.com.
  • 6 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400016, China; Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. Electronic address: xintian@cqmu.edu.cn.
PMID: 40300460 DOI: 10.1016/j.ejmech.2025.117613
Abstract

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.

Keywords

Antineuroinflammation; Antioxidant; Cinnamaldehyde; Epilepsy; Nipecotamide; Paeonol; Salicylaldehyde; Vanillin.

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