Synthesis and Screening of Substituted Thiosemicarbazone Derivatives: An Approach towards Novel Anticonvulsant Search

Priyanka      Singh; Jainendra      Jain; Reema      Sinha; Abdul      Samad; Rajeev      Kumar; Manav      Malhotra

Abstract

A series of thiosemicarbazones of halogen substituted benzaldehydes, benzophenone and acetophenone were synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established in three seizures models which includes maximal electroshock (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizures and minimal neurotoxicity test. Five compounds out of 21 exhibited protection in MES test while only one compound showed protection in scPTZ screen. Two compounds were found to be active in minimal clonic seizure (6Hz) model. Compound PS6 i.e. 2-(3-bromobenzylidene)- N-(4-chlorophenyl) hydrazinecarbothioamide emerged as the most active compound with MES ED50 of more than 50mg/kg and pI greater than 12, which is found to be better than the prototype drug, Phenytoin. The compound has shown neuroprotection in kainic acid model with IC50 value of 40.97 μM. It has also shown mild activation effect on CYP2D6 and CYP 2C9 enzymes, indicating the usefulness of thiosemicarbazones as anticonvulsants.

Keywords: Thiosemicarbazones, Anticonvulsant, ADD, Neurotoxicity, Pilocarpine, Kainic acid protection, NMDA, AED, MES, scPTZ, pI, Minimal clonic seizure, 4-Bromobenzaldehyde semicarbazone, aryl binding site, hydrogen boding area, neuroprotection, kainic acid, pilocarpine induced seizures, scPTZ ED50, isothiocyantes, prototype anticonvulsant, semicarbazones, status epilepticus, cytochrome P 450 isozymes, CYP2C9, CYP2D6, IC50, CYP2A6, Racine scale