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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis and Evaluation of Anticonvulsant Activities of 4-Phenylpiperidin- 2-one Derivatives

Author(s): Shi-Ben Wang*, Hui Liu, Guang-Yong Li, Kang Lei, Xiao-Jing Li, Zhe-Shan Quan and Xue-Kun Wang*

Volume 17, Issue 6, 2020

Page: [713 - 724] Pages: 12

DOI: 10.2174/1570180816666190710142848

open access plus


Background: Although Antiepileptic Drugs (AEDs) acting on various targets have been applied in the clinic, the efficacy and tolerance of AEDs in the treatment of epilepsy have not significantly improved. Therefore, there is an urgent need to develop some novel chemical moieties with a better safety profile and greater efficacy. We designed and synthesized twenty-seven 4- phenylpiperidin-2-one derivatives. This study aimed to investigate the potential use of a series of 4- phenylpiperidin-2-one derivatives as anticonvulsant drugs.

Methods: Two experimental methods, Maximal Electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, neurotoxicity (NT) was tested using the rotarod test.

Results: Compound 7-[4-(trifluoromethyl)phenyl]-6,7-dihydrothieno[3,2-b]pyridin-5-(4H)-one (11; MES, ED50 = 23.7 mg/kg, PI > 33.7; PTZ, ED50 = 78.1 mg/kg, PI > 10.0) showed the best anticonvulsant activity. The results of in vivo γ-aminobutyric Acid (GABA) estimation showed that compound 11 may have an effect on the GABA system. Compound 11 showed significant interactions with residues at the benzodiazepine (BZD)-binding site on GABAA receptors. Most target compounds have favorable blood brain barrier (BBB) permeability and oral bioavailability in predictions using silico molecular properties.

Conclusion: According to the in vivo and in silico studies, compound 11 stand out as potential anticonvulsant agents for further studies.

Keywords: Synthesis, anticonvulsant, MES, scPTZ, GABA, molecular docking studies.

Graphical Abstract
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