A series of alkyl/aryl/heteroaryl
piperazine derivatives (37-54) were designed and synthesized as potential
anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo
anticonvulsant activity in maximal electroshock (MES) and subcutaneous
pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the
piperazine ring displayed potent
anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited
anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent
anticonvulsant activity in MES test at the dose of 30mg/kg (0.5h) and 100mg/kg (4h) and also delivered excellent protection in sc-PTZ test (100mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of
epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked
seizures at the dose of 5mg/kg in kindled animals and significantly reduced oxidative stress better than standard
drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer
anticonvulsant lead molecule.