Ameltolide

Anticonvulsant activity of phthalimide was discovered in 2000 by molecular hybridization of thalidomide and ameltolide. In our present research we report some new 4-substituted derivatives of phthalimide with good activity against the tonic and clonic seizures. A series of novel 4-flurophthalimides designed using bioisosteric replacement were synthesized by condensation of 4-flurophthalic anhydride with appropriate arylamines. The purity of these compounds was determined by TLC and the chemical structures were confirmed by IR and ¹H-NMR spectroscopy. Anticonvulsant activity of prepared compounds was evaluated using MES and PTZ models. Some of the designed compounds significantly protected mice against the PTZ-induced seizure among which, compound 10 with lipophilic and flexible aromatic moiety was more potent than the reference drug phenytoin and was the most potent in this series of phthalimide derivatives. In the MES model, the prepared phthalimide did not show efficient activity. The prepared compounds are active in clonic seizure.

A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and H¹NMR. In-vivo screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/Kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock 4.2 program. Docking study has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel.