Novel pyrimidine based semicarbazones: Confirmation of four binding site pharmacophoric model hypothesis for antiepileptic activity.

Background: Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity.

Methods: The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation.

Results: The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor.

Conclusion: The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.