Design, synthesis and pharmacological evaluation of novel N-(2-(1, 1-dimethyl-5, 7-dioxo-4, 6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives as potential anticonvulsant agents

摘要

A series of new N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives (8a-i) and ethyl 2,2-dimethyl-1-(3-(2-(sulfonamido)ethyl)ureido) cyclopropanecarbox-ylate derivatives (9a-i) were designed, synthesized and evaluated for their anticonvulsant activities using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4-fluoroben- zenesulfonamide (8f) and N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4- methylbenzenesulfonamide (8e) have shown promising anticonvulsant activities in MES model. The most active compound 8f has shown the MES-induced seizures with ED50 value of 28.05 mg/kg and TD50 value of 561 mg/kg after intraperitoneal injection to mice, which provided compound 8f with a protective index (TD50/ED50) of 20 in the MES test. Further, rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds. (C) 2015 Elsevier Masson SAS. All rights reserved.