title: Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities.
abstract: This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 5a-p prepared from 3-amino-2-thiophenecarboxylic acid methyl ester. The final compounds were screened for their in vivo anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Neurotoxicity (NT) was tested using a rotarod test. The structure-anticonvulsant activity relationship analysis revealed that the most effective structural motif involves a substituted phenol, especially when substituted with a single chlorine, fluorine or trifluoromethyl group (at the meta-position), or two chlorine atoms. These molecules possessed high activity according to the MES and scPTZ models. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was 5-[3-(trifluoromethyl)phenoxy]thieno[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine (5o) with ED50 values of 11.5 mg/kg (MES) and 58.9 mg/kg (scPTZ). Furthermore, compound 5o was more effective in the MES and scPTZ tests than the well-known anticonvulsant drugs carbamazepine and ethosuximide.
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133000, China. 2010020146@ybu.edu.cn.
authors.forename: Shi-Ben
authors.initials: SB
authors.lastname: Wang
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133000, China. 2012010623@ybu.edu.cn.
authors.forename: Guang-Chun
authors.initials: GC
authors.lastname: Piao
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133000, China. 2012001040@ybu.edu.cn.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133000, China. zsquan@ybu.edu.cn.
authors.forename: Zhe-Shan
authors.initials: ZS
authors.lastname: Quan
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004195:Disease Models, Animal; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D011743:Pyrimidines; C030986:pyrimidine