Background: Epilepsy is a serious and common neurological disorder threatening the
health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present
many limitations. These limitations prompted the development of more safer and effective AEDs.
Methods: A series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4-
one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and
tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole
(scPTZ). Neurotoxicity was determined by the rotarod test.
Results: Among them, the most potent 4e displayed high protection against MES-induced seizures
with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective
index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the
NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results.
Conclusion: Stiripentol is a good lead compound for further structural modification. Compound 4e
was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition
was involved in the mechanism of action of 4e.