Background: Hydrazone core is a versatile structural linker for the development of various
classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of
thiophene based hydrazones according to the antiepileptic drug development program protocol.
Methods: The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in
mice were performed. Additionally, the active compounds in the screening test were subsequently subjected
to the maximal electroshock-induced seizure test that allowed determination of their median effective
doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal
slice culture neuroprotection assay.
Results: Among the synthesized compounds, 1-(thiophen-2-yl) ethylidene] hydrazine carboxamides
(THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum
anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz-
Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced
seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a
good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate.
THb (100μM) was also found to be effectively suppressing network hyperexcitability in the in vitro mECHC
spontaneous bursting model, as determined by effects on spontaneous burst activity and duration.
Conclusion: The suggested pharmacophore model for lead compounds from thiophene based hydrazones
is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding
domain-carboxamide or carbothioamide unit.