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

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• 作者：Krzysztof Kami¨½ski ; Jolanta Obniska ; Iwona Chlebek ; Beata Wiklik ; Sabina Rzepka
• 关键词：N-Mannich bases ; 3-Phenylpyrrolidine-2 ; 5-diones ; Succinimides ; Anticonvulsant activity ; In vivo studies ; In vitro studies ; Epilepsy
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 November, 2013
• 年：2013
• 卷：21
• 期：21
• 页码：6821-6830
• 全文大小：626 K

文摘

The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (<strong class=""boldFont"">9astrong>-<strong class=""boldFont"">dstrong>), 3-(2-chlorophenyl)- (<strong class=""boldFont"">10astrong>-<strong class=""boldFont"">dstrong>), 3-(3-chlorophenyl)- (<strong class=""boldFont"">11astrong>-<strong class=""boldFont"">dstrong>) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (<strong class=""boldFont"">12astrong>-<strong class=""boldFont"">dstrong>) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (<strong class=""boldFont"">5strong>-<strong class=""boldFont"">8strong>), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds <strong class=""boldFont"">9astrong>-<strong class=""boldFont"">dstrong>, <strong class=""boldFont"">10astrong>-<strong class=""boldFont"">dstrong>, <strong class=""boldFont"">11astrong>-<strong class=""boldFont"">dstrong> and <strong class=""boldFont"">12astrong>-<strong class=""boldFont"">dstrong> 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 (<strong class=""boldFont"">10cstrong>) which showed ED<sub>50sub> value of 37.64 mg/kg. It should be stressed that this molecule along with <strong class=""boldFont"">9astrong>, <strong class=""boldFont"">9dstrong> and <strong class=""boldFont"">10dstrong> showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds <strong class=""boldFont"">9astrong>, <strong class=""boldFont"">9dstrong> and <strong class=""boldFont"">10dstrong> were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule <strong class=""boldFont"">9dstrong> an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.