Design, Synthesis, and Anticonvulsant Activity Evaluation of 4-(3-Alkoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-ones
Design, Synthesis, and Anticonvulsant Activity Evaluation of 4-(3-Alkoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-ones
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4-(3-烷氧基-苯基)-2,4-二氢-[1,2,4]三唑-3-酮类化合物的设计、合成及抗惊厥活性评价
DOI：
10.1002/ardp.201200201
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发表时间：
2013-02-01
影响因子：
5.1
通讯作者：
Quan, Zhe-Shan
中科院分区：
文献类型：
--
作者：
Shu, Bing;Zheng, Yan;Quan, Zhe-Shan
以合适的合成路线合成了一系列4-(3-alkoxy-phenyl)-2，4-dihydro-[1，2，4]triazol-3-ones，并在最大电击试验中进行了实验评价；通过旋转棒神经毒性试验评价了它们的神经毒性。化合物的结构经IR、MS、1H-核磁共振和元素分析确证。在最大电击试验中，所有目标化合物均表现出不同程度的抗惊厥活性。4-(3-Benzyloxy-phenyl)-2，4-dihydro-[1，2，4]triazol-3-one(4I)是最有希望的化合物，其ED50值为30.5 mg/kg，保护指数(PI)为18.63，安全性高于标准卡马西平(PI=6.45)。此外，化合物4I对戊四氮和3-巯基丙酸所致惊厥的抑制作用表明其广谱活性，其作用机制可能与其抑制电压门控离子通道和调节GABA能活动有关。
A series of 4-(3-alkoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-ones were synthesized using the appropriate synthetic route and evaluated experimentally in the maximal electroshock test; their neurotoxicities were evaluated by the rotarod neurotoxicity test. The structures of these compounds were confirmed by IR, MS, 1H-NMR, and elementary analysis. All target compounds exhibited anticonvulsant activity to varying degrees in the maximal electroshock test. 4-(3-Benzyloxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one (4i) was the most promising compound with an ED50 value of 30.5mg/kg and a protective index (PI) of 18.63, showing a higher safety than the standard carbamazepine (PI=6.45). In addition, the potency of compound 4i against seizures induced by pentylenetetrazole and 3-mercaptopropionic acid suggested its broad-spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might be involved in its anticonvulsant activity.