Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2, 5-dione. (1st November 2016)

• Record Type: Journal Article
• Authors: Rybka, Sabina; Obniska, Jolanta; Rapacz, Anna; Filipek, Barbara; Żmudzki, Paweł
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 31:Number 6(2016:Dec.)
• Page Start: 1038
• Page End: 1047
• Publication Date: 2016-11-01
• Subjects: Anticonvulsant activity -- in vitro studies -- in vivo studies -- pyrrolidine-2, 5-diones; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2015.1088842
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Synthesis and anticonvulsant properties of 26 new N -Mannich bases of 3-benzhydryl-(5 –17 ) and 3-isopropyl-pyrrolidine-2, 5-diones (18 –30 ) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole ( sc PTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2, 5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2, 5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2, 5-dione (9 ) with ED5 0 value =42.71 mg/kg (MES), ED5 0 value >150 mg/kg ( sc PTZ), and N -[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2, 5-dione (13 ) with ED5 0 value =101.46 mg/kg (MES) and ED5 0 value =72.59 mg/kg ( sc PTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and13 ), their influence on Nav 1.2 andl -type calcium channel was evaluated in vitro.