Synthesis and biological properties of new N-Mannich bases derived from 3-methyl-3-phenyl- and 3,3-dimethyl-succinimides. Part V

• Library of 24 new compounds as potential anticonvulsants have been synthesized.
• Anticonvulsant screening was performed using in vivo MES and scPTZ seizures tests.
• The most active compound were more potent than model anticonvulsants.
• Several molecules revealed antimutagenic activity in the Vibrio harveyi test.

Twenty four new 1-[(4-phenylpiperazin-1-yl)-methyl]- derivatives of 3-phenyl-3-methyl- (6–17) and 3,3-dimethyl-pyrrolidine-2,5-diones (18–29) have been synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotorod screen. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds revealed protection in electrically induced seizures. From these molecules seven compounds were tested in rats after oral administration (MES test). In the whole series the most effective in rats were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with ED50 value of 7.78 mg/kg, it's 3-chlorophenyl- (10) and 3,4-dichlorophenyl- (12) analogs with ED50 values of 27.93 mg/kg and 15.11 mg/kg, respectively. To explain the possible mechanism of action for the most active derivatives 8, 10 and 12 the influence on NaV1.2 sodium channel currents were evaluated in vitro. The results of electrophysiological studies showed higher inhibition of NaV1.2 currents in comparison with phenytoin used as a model antiepileptic drug active in electrically induces seizures. Additionally, eleven 3-phenyl-3-methyl-pyrrolidine-2,5-diones as more promising in the anticonvulsant screening were evaluated in the Vibrio harveyi test to estimate their anti/mutagenic activity.

Several compounds showed higher activity in the maximal electroshock seizure test (MES) in rats than phenytoin used as model antiepileptic drug. These molecules act as NaV1.2 sodium channel current blockers.Figure optionsDownload as PowerPoint slide