title: Design, synthesis and protection against pentylenetetrazole-induced seizure of N-aryl derivatives of the phthalimide pharmacophore.
abstract: A series of compounds including N-aryl substituents of phthalimide and 4-nitrophthalimide were synthesized and evaluated for their anticonvulsant properties. The in vivo screening data suggest that all the analogs have the ability to protect against pentylenetetrazole-induced seizures. These compounds exerted their maximal effects 30 min after administration. The most potent compound in both, tonic and clonic seizure was 1-naphthyl derivative (comp. 6), which was more active than the reference drug known as Phenytoin. Using an open pore model of the Na channel, these anticonvulsants were docked in the active site and examined in relation to the residues identified by mutagenesis as important for their binding energies. Docking studies revealed that all compounds (1-13) interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and additional hydrophobic interactions with domain I and II in the channel's inner pore.
authors: Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, 19419, Iran. adavood@iaups.ac.ir
authors: Asghar
authors: A
authors: Davood
authors: Hamed
authors: H
authors: Shafaroodi
authors: Mohsen
authors: M
authors: Amini
authors: Alireza
authors: A
authors: Nematollahi
authors: Mehrshad
authors: M
authors: Shirazi
authors: Maryam
authors: M
authors: Iman
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000235:genetics; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010433:Pentylenetetrazole; D010672:Phenytoin / Q000494:pharmacology; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009574:Nitro Compounds; D010797:Phthalimides; D010672:Phenytoin; C082211:4-nitrophthalimide; D010433:Pentylenetetrazole