title: Design, synthesis and biological evaluation of new hybrid anticonvulsants derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives.
abstract: The purpose of this study was to synthesize the library of 33 new N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamides, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamides, and 2-(2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. The coupling reaction of the 2-(2,5-dioxopyrrolidin-1-yl)propanoic acid, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanoic acid, or 2-(2,5-dioxopyrrolidin-1-yl)butanoic acid with the appropriately substituted benzylamines in the presence of the coupling reagent, N,N-carbonyldiimidazole (CDI) generated the final compounds 4-36. Spectral data acquired via (1)H NMR, (13)C NMR, and LC-MS confirmed the chemical structures of the newly prepared compounds. The initial anticonvulsant screening was performed in mice intraperitoneally (ip), using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The rotarod test determined the acute neurological toxicity (NT). The results of preliminary pharmacological screening revealed that 25 compounds showed protection in half or more of the animals tested in the MES and/or scPTZ seizure models at the fixed dose of 100mg/kg. The broad spectra of activity across the preclinical seizure models displayed compounds 4, 7, 8, 13, 15-18, 24, and 26. The quantitative pharmacological studies in mice demonstrated the highest protection for compounds 4 (ED50 MES=67.65 mg/kg, ED50scPTZ=42.83 mg/kg); 8 (ED50 MES=54.90 mg/kg, ED50scPTZ=50.29 mg/kg); and 20 (ED50scPTZ=47.39 mg/kg). These compounds were distinctly more potent and provided better safety profiles in the rotarod test compared to valproic acid or ethosuximide, which were used as model AEDs. Compound 8 underwent only a slight metabolic change by the human liver microsomes (HLMs), and also did not affect the activity of human cytochrome P450 isoform, CYP3A4, in the in vitro assays.
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland. Electronic address: k.kaminski@uj.edu.pl.
authors: Krzysztof
authors: K
authors: Kamiński
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors: Anna
authors: A
authors: Rapacz
authors: Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8 Str., 20-090 Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2 Str., 20-950 Lublin, Poland.
authors: Jarogniew J
authors: JJ
authors: Łuszczki
authors: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors: Gniewomir
authors: G
authors: Latacz
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors: Jolanta
authors: J
authors: Obniska
authors: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors: Katarzyna
authors: K
authors: Kieć-Kononowicz
authors: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors: Barbara
authors: B
authors: Filipek
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry; D003292:Convulsants / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004597:Electroshock; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000008:administration & dosage; D011422:Propionates / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000927:Anticonvulsants; D001596:Benzylamines; D003292:Convulsants; D007093:Imidazoles; D011422:Propionates; D011759:Pyrrolidines; D054852:Small Molecule Libraries; C006900:N,N-carbonyldiimidazole; D010433:Pentylenetetrazole
keywords: Anticonvulsant activity; Hybrid compounds; In vitro studies; In vivo studies; Metabolic stability; Pyrrolidine-2,5-dione