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

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.