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
  • 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: [email protected].
  • 5. School of Pharmacy, North Sichuan Medical College, Nanchong, 637000, China. Electronic address: [email protected].
  • 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: [email protected].
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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