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Synthesis and Evaluation of N-substituted (Z)-5-(Benzo[d][1,3]dioxol-5- ylmethylene)-2-Thioxothiazolidin-4-one Derivatives and 5-Substituted- Thioxothiazolidindione Derivatives as Potent Anticonvulsant Agents

[ Vol. 18 , Issue. 10 ]

Author(s):

Shiyang Dong, Yanhua Liu, Jun Xu*, Yue Hu, Limin Huang and Zengtao Wang*   Pages 798 - 807 ( 10 )

Abstract:


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.

Keywords:

Thioxothiazolidindione derivatives, synthesis, anticonvulsant, NaV1.1 channel, stiripentol, patch-clamp.

Affiliation:

College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004

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