Synthesis and Determination of Lipophilicity, Anticonvulsant Activity, and Preliminary Safety of 3‐Substituted and 3‐Unsubstituted N‐[(4‐Arylpiperazin‐1‐yl)alkyl]pyrrolidine‐2, 5‐dione Derivatives. (14th November 2017)

• Record Type: Journal Article
• Authors: Rybka, Sabina; Obniska, Jolanta; Żmudzki, Paweł; Koczurkiewicz, Paulina; Wójcik‐Pszczoła, Katarzyna; Pękala, Elżbieta; Bryła, Adrian; Rapacz, Anna
• Is Part Of: ChemMedChem. Volume 12:Number 22(2017)
• Page Start: 1848
• Page End: 1856
• Publication Date: 2017-11-14
• Subjects: anticonvulsant agents -- epilepsy -- lipophilicity -- liquid chromatography -- nitrogen heterocycles; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700539
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: A new series of 1, 3‐substituted pyrrolidine‐2, 5‐dione derivatives as potential anticonvulsant agents are described. Initial pharmacological screening of these compounds was performed by using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. Quantitative pharmacological research revealed that the most promising compounds were N ‐[{4‐(3‐trifluoromethylphenyl)piperazin‐1‐yl}propyl]‐3‐benzhydrylpyrrolidine‐2, 5‐dione monohydrochloride (11 ) with a ED50 value of 75.9 mg kg −1 (MES test) and N ‐[{4‐(3, 4‐dichlorophenyl)piperazin‐1‐yl}ethyl]‐3‐methylpyrrolidine‐2, 5‐dione monohydrochloride (18 ) with ED50 =88.2 mg kg −1 (MES test) and ED50 =65.7 kg mg −1 (scPTZ test). These compounds displayed a more beneficial protective index than well‐known antiepileptic drugs. A plausible mechanism of action of compounds11 and18 [molecule11 blocked the sodium channel (site 2) and18 blocked both the 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 by using UPLC–MS. Abstract : Seize the moment : New derivatives of pyrrolidine‐2, 5‐dione are synthesized and evaluated for their anticonvulsant activity. Several compounds display a more beneficial protective index than well‐known antiepileptic drugs. A plausible mechanism of action, preliminary safety in vitro, and the lipophilicity of the compounds are also evaluated.