Mechanochemical synthesis and anticonvulsant activity of 3-aminopyrrolidine-2,5-dione derivatives

A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple solvent-based reaction and a mechanochemical aza-Michael reaction of maleimide or its N-substituted derivatives with selected amines. The structure of the compounds was confirmed by spectroscopic methods (NMR, FT-IR, HPLC, ESI-MS, EA and XRD for four compounds). The cytotoxic activity of the succinimide derivatives was evaluated using HepG2 cells for hepatocytotoxicity and SH-SY5Y cells for neurocytotoxicity. None of the studied compounds showed hepatocytotoxicity and two showed neurocytotoxicity. Initial anticonvulsant screening was performed in mice using the psychomotor seizure test (6 Hz, 32 mA). The selected compounds were evaluated in the following acute models of epilepsy: the maximal electroshock test, psychomotor seizure test (6 Hz, 44 mA), subcutaneous pentylenetetrazole seizure test, and acute neurotoxicity (rotarod test). The most active compound 3-((4-chlorophenyl)amino)pyrrolidine-2,5-dione revealed antiseizure activity in all seizure models (including pharmacoresistant seizures) and showed better median effective doses (ED50) and protective index values than the reference compound, ethosuximide. Furthermore, 3-(benzylamino)pyrrolidine-2,5-dione and 3-(phenylamino)pyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz and MES tests, and 3-(butylamino)−1-phenylpyrrolidine-2,5-dione and 3-(benzylamino)−1-phenylpyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz test. All active compounds demonstrated low in vivo neurotoxicity in the rotarod test and yielded favourable protective indices.