Synthesis and anticonvulsant activity of new N-Mannich bases derived from 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones. Part II.
Synthesis and anticonvulsant activity of new N-Mannich bases of 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones have been described. Initial anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that majority of compounds were effective in the MES test. Only seven molecules showed protection in the scPTZ test. The quantitative evaluation in the MES seizures after oral administration into rats showed that the most active were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (14) with ED(50) of 7.4mg/kg and 1-[{4-(3-bromophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (16) with ED(50) of 26.4mg/kg. These molecules were more potent and also less neurotoxic than phenytoin which was used as reference antiepileptic drug.
Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. mfobnisk@cyf-kr.edu.pl
Jolanta
J
Obniska
Sabina
S
Rzepka
Krzysztof
K
Kamiński
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D008297:Male; D008352:Mannich Bases / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000927:Anticonvulsants; D008352:Mannich Bases; D013388:Succinimides; D010433:Pentylenetetrazole