Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models

Document Type: Original Article


1 Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran

2 Department of Pharmaceutics, Faculty of pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran

3 Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

4 Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran

5 Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran


Objective(s): Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents.
Materials and Methods: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models.
Results: The in vivo screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds 3 and 9 elevated clonic seizure thresholds at 30 min which were more active than the standard medicine phenytoin. Compounds 3, 6, 7, 11, 13 and 14 with 100% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound 3. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore.
Conclusion: Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures.


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