Design and optimization of nafimidone-inspired hybrid scaffolds targeting Na_V1.2 for antiepileptic therapy with reduced cardiac liability.

Authors

Shahenda Mahmoud, Tarek F El-Moselhy, Eman A El-Bastawissy, Abeer Salama, Mahmoud A A Ibrahim, Shahzeb Khan, Sreekanth Pentlavalli, Tarad Abalkhail, Mohammed A M Salih, Sun Huang, Gerald W Zamponi, Peter A Sidhom

Published in

Bioorganic chemistry. Volume 181. Pages 110359. Aug 09, 2026. Epub Aug 09, 2026.

Abstract

Epilepsy remains a major neurological disorder in need of safer and more effective antiepileptic agents. In this study, nineteen nafimidone-guided derivatives were designed, synthesized, and biologically evaluated to identify new anticonvulsant leads with improved efficacy, brain accessibility, and safety. Initial in vivo screening in the MES model identified compounds 11b and 12a among the most active derivatives, both affording 100% protection against MES-induced seizures at 30 mg/kg. Quantitative anticonvulsant testing established 12a as the most potent lead, with an ED₅₀ of 3.12 mg/kg and a protective index >160.3, exceeding both nafimidone (ED₅₀ 7.40 mg/kg; PI 16.56) and phenytoin (ED₅₀ 6.14 mg/kg; PI 18.3), while 11b showed an ED₅₀ of 14.31 mg/kg and PI >34.94. Electrophysiological studies confirmed effective Na_V1.2 blockade, with 12a showing the highest potency (IC₅₀ = 16.93 ± 1.33 μM) versus11b (31.21 ± 1.88 μM) and nafimidone (43.12 ± 1.27 μM), together with preferential inactivated-state inhibition. Both compounds restored seizure-associated neurochemical imbalance in PTZ-kindled brains, increasing GABA by 365% (11b) and 353% (12a) and reducing glutamate by 28%, outperforming nafimidone. Oxidative stress was also markedly attenuated, as reflected by increased GSH (+38% and + 40%) and reduced MDA (-43% and -41%) for 11b and 12a, respectively. In vitro antioxidant assays revealed a distinct antioxidant activity for 11b, which showed strong FRAP activity (1458.90 ± 6.86 μM TE/mg), whereas 12a displayed minimal radical-scavenging activity, indicating a more channel-focused profile. Importantly, both leads exhibited favorable CNS drug-like behavior, with high PAMPA-BBB permeability and efficient in vivo brain exposure; 12a showed the highest brain/plasma ratios (3.42 at 0.25 h and 3.97 at 0.5 h). Both compounds also showed minimal CYP3A4, CYP2D6, and CYP2C9 inhibition at 50 μM, reduced Na_V1.5-related liability, and improved cytotoxic and hepatotoxic profiles relative to nafimidone and phenytoin, with 12a showing the most favorable hepatic safety pattern. Collectively, these findings identify 12a as the most promising anticonvulsant lead, combining potent Na_V1.2-targeted seizure protection, excellent brain exposure, improved CYP inhibition profile, and reduced hepatic liability, while 11b emerges as a complementary dual-action scaffold with stronger antioxidant activity and PTZ-protective features.

PMID:
42603541
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.

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