title: Design, synthesis and anticonvulsant activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides.
abstract: The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED50 MES=96.9mg/kg, ED50scPTZ=75.4mg/kg, ED50 6Hz=44.3mg/kg) which showed TD50=335.8mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES=3.5, PI scPTZ=4.4, PI 6Hz=7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna, 30-688 Kraków, Poland. Electronic address: k.kaminski@uj.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna, 30-688 Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna, 30-688 Kraków, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D015220:Calcium Channels / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy*
chemical_list: D000577:Amides; D000927:Anticonvulsants; D015220:Calcium Channels; D011759:Pyrrolidines
keywords: Anticonvulsant activity; Hybrid compounds; In vitro studies; In vivo studies; Pyrrolidine-2,5-dione