Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and its 3-methyl-, 3-isopropyl,and 3-benzhydryl analogs

The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6 Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED₅₀ = 41.0 mg/kg), scPTZ (ED₅₀ = 101.6 kg/mg), and 6 Hz (ED₅₀ = 45.42 mg/kg) tests. This compound displayed more beneficial protection index (PI) than antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. In vitro studies for compound 15 were conducted and provided information that its possible mechanism of action is related to blocking of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels.