Shiyang Dong, Yanhua Liu, Jun Xu
Nov 19, 2019
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Quality indicators
Journal
CNS & neurological disorders drug targets
Abstract
BACKGROUND Epilepsy is a serious and common neurological disorder threatening health of human. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations that 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 was designed, synthesized and tested for anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by rotarod test. RESULTS Among of them, the most potent 4e displayed high protection against the MES-induced seizures with 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. The 4e clearly inhibits the NaV1.1 channel in vitro experiment. The molecular docking study was made to exploit the results. CONCLUSION Stiripentol is a good lead compound for further structural modification. We have got the compound 4e, which display remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the action mechanism of 4e.