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2,2-二甲基-1-(2-取代肼基甲酰胺基)环丙烷羧酸乙酯衍生物的合成及其抗惊厥活性

Synthesis and anticonvulsant activity of ethyl 2,2-dimethyl-1-(2-substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives.

作者信息

Zhong Min, Zhang Yongmin, He Xianran

机构信息

Wuhan Economic and Technological Development Zone, School of Chemical and Environmental Engineering, Jianghan University, Wuhan, 430056, China.

出版信息

Chem Biol Drug Des. 2014 Aug;84(2):234-41. doi: 10.1111/cbdd.12310. Epub 2014 Mar 26.

Abstract

In this study on the development of new anticonvulsants, fourteen ethyl 2,2-dimethyl-1-(2-substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock-induced seizures with ED50 value of 9.2 mg/kg and TD50 value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD50/ED50 ) of 42.1 in the maximal electroshock test.

摘要

在这项关于新型抗惊厥药开发的研究中,合成了十四种2,2 - 二甲基 - 1 - (2 - 取代肼基甲酰胺基)环丙烷羧酸乙酯衍生物,并使用最大电休克、皮下注射戊四氮筛选法测试其抗惊厥活性,这两种方法是早期鉴定候选抗惊厥药时应用最广泛的癫痫发作模型。通过转棒试验测定它们的神经毒性。在用于抗惊厥评估的两种模型中,化合物6f和6k均显示出有前景的抗惊厥活性。活性最高的化合物6k对小鼠腹腔注射后,在最大电休克诱导的癫痫发作中,ED50值为9.2 mg/kg,TD50值为387.5 mg/kg,在最大电休克试验中为化合物6k提供了42.1的保护指数(TD50/ED50)。

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