含有三唑的苯并[d]噁唑类衍生物的合成及其抗惊厥活性评价  

Synthesis and Evaluation of the Anticonvulsant Activities of Triazole-Containing Benzo[d]oxazoles

作　　者：谭月德 何晓艳[1] 饶保奇 程彬彬[1] 宋明霞[1] 邓先清[1] 

机构地区：[1]井冈山大学医学部基础医学与药学学院,吉安343009

出　　处：《有机化学》2016年第10期2449-2455,共7页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.21562028);江西省自然科学基金项目(Nos.20151BAB213008;20142BAB215022);江西省教育厅科技计划项目(No.GJJ14570);井冈山大学博士启动基金(No.JZB1316)资助项目~~

摘　　要：设计并合成了一系列三唑-苯并噁唑类化合物,采用最大电惊厥模型(MES)和皮下戊四唑模型(Sc-PTZ)评价了其抗惊厥活性,用旋转棒法测定了其神经毒性.药理实验显示,大部分化合物在MES和Sc-PTZ模型中均表现出不同程度的抗惊厥活性,其中2-(3-氟苄基)硫基-5-(4H-1,2,4-三唑-4-基)苯并[d]噁唑(5i)的抗惊厥活性最强,其在MES和Sc-PTZ模型中的半数有效剂量ED_(50)分别为11.4和31.7 mg/kg,半数神经毒性剂量TD_(50)为611.0 mg/kg,保护指数PI值分别为53.6和19.3,明显优于对照药卡马西平和丙戊酸钠.GABA合成酶抑制剂硫代氨基脲的预处理使得化合物5i的抗惊厥活性明显下降,说明化合物5i的抗惊厥作用至少部分是通过作用于GABA神经能系统譬如增加GABA神经递质来实现的.A series of 2-thioalkyl-5-（4H-1,2,4-triazol-4-yl）benzo[d]oxazoles were designed and synthesized. Their anticon-vulsant activities were evaluated using maximal electroshock shock （MES） and subcutaneous pentylenetetrazole （scPTZ） seizure models in mice. The neurotoxicity was evaluated with rotarod test. The pharmacology results showed that most compounds exhibited anticonvulsant activity in MES and Sc-PTZ models. Among them, 2-（3-fluobenzyl）thio-5-（4H-1,2,4-triazol-4-yl）benzo[d]oxazole （5i） was the most potent with ED50 value of 11.4 and 31.7 mg/kg in MES and Sc-PTZ models, respectively. The TD50 value of 5i was 611.0 mg/kg, which resulted in the protective index （PI=TD50/ED50） value of 53.6 and 19.3. The pretreatment of thiosemicarbazide （an inhibitor of γ-aminobutyric acid synthesis enzyme） significantly decreased the active of 5i in MES, which suggested that the GABAergic system may contribute at least in part to the anticonvulsive action.

关 键 词：抗癫痫药 抗惊厥 苯并[d]噁唑 三唑 MES Sc-PTZ 

分 类 号：R914.5[医药卫生—药物化学] TQ463.53[医药卫生—药学]