Synthesis, Physicochemical, and Anticonvulsant Properties of New N-Mannich Bases Derived from Pyrrolidine-2,5-dione and Its 3-Methyl Analog

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 = 16.13mg/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.