US EPA

2453304 

Journal Article 

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

Kaminski, K; Obniska, J; Chlebek, I; Wiklik, B; Rzepka, S 

2013 

Yes 

Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391 

21 

21 

6821-6830 

English 

23993970 

10.1016/j.bmc.2013.07.029 

WOS:000325164500060 

http://dx.doi.org/10.1016/j.bmc.2013.07.029
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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 37.64 mg/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. (C) 2013 Elsevier Ltd. All rights reserved. 

N-Mannich bases; 3-Phenylpyrrolidine-2,5-diones; Succinimides; Anticonvulsant activity; In vivo studies; In vitro studies; Epilepsy