title: 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.
abstract: 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.
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 430071, PR China. Electronic address: xhy78@whu.edu.cn.
authors.forename: Xuechuan
authors.initials: X
authors.lastname: Hong
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004597:Electroshock; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D012640:Seizures / Q000188:drug therapy*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D003508:Cycloheptanes; C000603213:N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro(2.4)heptan-6-yl)ethyl); D013141:Spiro Compounds
keywords: Anticonvulsant; MES test; Sulfonamide; scPTZ test