4 years ago

Synthesis, determination of the lipophilicity, anticonvulsant activity and preliminary safety of new derivatives of N-[(4-arylpiperazin-1-yl)-alkyl]-pyrrolidine-2,5-dione

Anna Rapacz, Adrian Bryła, Elżbieta Pękala, Paweł Żmudzki, Paulina Koczurkiewicz, Jolanta Obniska, Sabina Rybka, Katarzyna Wójcik-Pszczoła
A new series of derivatives of 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents are described in this paper. Initial pharmacological screening for these compounds was performed using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. A quantitative pharmacological research revealed that the most promising compound were N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-3-benzhydryl-pyrrolidine-2,5-dione monohydrochloride (11) with ED50=75.9 mg/kg (MES test) and N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-ethyl]-3-methyl-pyrrolidine-2,5-dione monohydrochloride (18) with ED50=88.2 mg/kg (MES test) and ED50=65.7 kg/mg (scPTZ test). These compounds displayed a more beneficial protective index than well-known antiepileptic drugs. The plausible mechanism of the action of the compounds 11 and 18 (molecule 11 blocked sodium channel (site 2) and 18 both sodium (site 2) and L-type calcium channels) and their preliminary safety in vitro were evaluated. Besides, the lipophilicity of all synthesized compounds was determined using the UPLC/MS method.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700539

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