Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones

• Published in: Bioorganic & medicinal chemistry 2013-11, Vol.21 (21), p.6821-6830
• Main Authors: Kamiński, Krzysztof, Obniska, Jolanta, Chlebek, Iwona, Wiklik, Beata, Rzepka, Sabina
• Format: Article
• Language: English
• Subjects: 3-Phenylpyrrolidine-2,5-diones; Administration, Oral; Animal models; Animals; Anticonvulsant activity; anticonvulsants; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; chemistry; cytochrome P-450; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Disease Models, Animal; Drug Design; Electroshock; Epilepsy; formaldehyde; Humans; In vitro studies; In vivo studies; Male; Mannich Bases - chemistry; Mannich Bases - pharmacology; Mannich Bases - therapeutic use; Mice; Microsomes, Liver - enzymology; Motor Activity - drug effects; N-Mannich bases; oral administration; Pentylenetetrazole - toxicity; Protein Binding; Pyrrolidines - chemistry; Rats; Rats, Sprague-Dawley; screening; secondary amines; seizures; Seizures - chemically induced; Seizures - drug therapy; Seizures - prevention & control; Structure-Activity Relationship; Succinimides; toxicity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.07.029

The library of sixteen new N-Mannich bases of 3-phenyl-pyrrolidine-2,5-diones were synthesized and tested in vivo for anticonvulsant activity. Several compounds were active in different animal models of epilepsy. The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a–d), 3-(2-chlorophenyl)- (10a–d), 3-(3-chlorophenyl)- (11a–d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a–d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5–8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a–d, 10a–d, 11a–d and 12a–d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.