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.
Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase
