Computational study and synthesis of a new class of anticonvulsants with 6 Hz psychomotor seizure test activity: 2-(1,3-benzodioxol-5-yloxy)-N'- [substituted]-acetohydrazides

Background: About 50 million epileptic cases worldwide and 12 million in India are reported. Currently available drugs yield acceptable control of seizure in 60–70% patients and show many toxic effects. These actualities provoked the search of novel, more efficacious and safer anticonvulsants. Objective: Concatenation of 2-(1,3-benzodioxol-5-yloxy)-N'-[substituted]-acetohydrazides SA 1-10 was designed by molecular hybridization, optimized by computational study and synthesized with the objective of obtaining a prototype of potent anticonvulsant molecules especially active against partial seizures. Methods: Computational study was performed to calculate the pharmacophoric design, projection of the pharmacokinetic parameters and docking scores of the titled compounds with molecular targets of epilepsy. The anticonvulsant activity was ascertained by 6 Hz psychomotor seizure test. Minimal motor impairment showing neurotoxicity was assessed using Rotarod test. Results: Titled compounds possessed the indispensable elements of pharmacophore and displayed good binding affinity with molecular targets of epilepsy, such as GABA (A) alpha-1 & delta receptor, glutamate receptor, Na+ /H+ exchanger and GABA- aminotransferase in docking studies. The most potent compound of the concatenation was 2-(1,3-benzodioxol-5- yloxy)-N'-[4-(4-chlorophenoxy)benzylidene]-acetohydrazide SA 4, showing 100% protection at four different time points with ED50 value 146.8 mg/kg at a TPE of 1 h in mice. Conclusion: The protection shown in 6 Hz test is implicated as the compound's ability to control partial seizures. Thus, the titled compounds can be considered as potential prototype candidates for antiepileptic therapy against partial seizures.