Design, synthesis and anticonvulsant evaluation of novel N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothio amides

Thirty six new N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothioamides were synthesized and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity was established in three seizure models i.e. MES, scMET and 6 Hz model. The most active compound was 2-[4-(4-chlorophenoxy)benzylidene]-N-(4-fluorophenyl)hydrazinecarbothioamide PC 31 which showed 100% protection at 0.5 h in the 6 Hz test. Compound 2-[4-(4-bromophenoxy) benzylidene]-N-(4-bromophenyl) hydrazinecarbothioamide PC 23 was found to be active in both the MES and 6 Hz test. A computational study was carried out from calculation of a pharmacophore pattern and the prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta and GABA (A) alpha-1 receptors, in the Lamarckian genetic algorithm based on flexible docking studies.

Graphical abstractThirty six novel N-(4-substituted phenyl)-2-[4-(substituted)benzylidene] hydrazinecarbothioamides were synthesized and evaluated for anticonvulsant activity. Their computational studies were also reported. 2-[4-(4-Chlorophenoxy)benzylidene]-N-(4-fluorophenyl)hydrazinecarbothioamide PC 31emerged as most active compound of the series.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel hydrazinecarbothioamides PC 1–36 were reported as potential anticonvulsants. ► Compound PC 31 was the most active compound showing 100% protection in 6 Hz test. ► PC 31 showed ED50 > 200 mg/kg (6 Hz test) and TD50 > 500 mg/kg at a TPE of 0.5 h. ► Hydrazinecarbothioamides exhibited good binding properties with epilepsy molecular targets.