title: Synthesis, physicochemical, and anticonvulsant properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and its 3-methyl analog.
abstract: A series of 22 new N-[(4-phenylpiperazin-1-yl)-methyl]-3-methyl-pyrrolidine-2,5-dione and pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their anticonvulsant activities in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that seven compounds were effective in the MES or/and scPTZ seizure tests. The quantitative evaluation in both tests after i.p. administration into mice revealed that the most active compounds were N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-methyl]-3-methylpyrrolidine-2,5-dione (12) with ED50  = 16.13 mg/kg (MES), ED50  = 133.99 mg/kg (scPTZ) and N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-methyl]-pyrrolidine-2,5-dione (23) with ED50  = 37.79 mg/kg (MES), ED50  = 128.82 mg/kg (scPTZ), whereas N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-pyrrolidine-2,5-dione (24) was effective only in the MES test with ED50  = 16.37 mg/kg. These molecules showed higher potency and also lower neurotoxicity than the reference antiepileptic drugs such as ethosuximide and valproic acid.
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Jagiellonian University, Medical College, Kraków, Poland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rybka
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004597:Electroshock; D005013:Ethosuximide / Q000494:pharmacology; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000523:psychology; D010433:Pentylenetetrazole; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D045442:Rotarod Performance Test; D012640:Seizures / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D011759:Pyrrolidines; D005013:Ethosuximide; D014635:Valproic Acid; D010433:Pentylenetetrazole
keywords: Anticonvulsant activity; In vivo studies; Mannich bases