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.