Synthesis and Evaluation of Halogenated 5-(2-Hydroxyphenyl)pyrazoles as Pseudilin Analogues Targeting the Enzyme IspD in the Methylerythritol Phosphate Pathway
Synthesis and Evaluation of Halogenated 5-(2-Hydroxyphenyl)pyrazoles as Pseudilin Analogues Targeting the Enzyme IspD in the Methylerythritol Phosphate Pathway
复制标题
甲基赤藓糖醇磷酸途径中 IspD 酶靶向假蛋白类似物卤代 5-(2-羟基苯基)吡唑的合成与评价
DOI：
10.1021/acs.jafc.9b08057
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发表时间：
2020
影响因子：
6.1
通讯作者：
Zhang Aidong
中科院分区：
文献类型：
--
作者：
Wang Jili;Zhou Yaqing;Wang Xiuwen;Duan Lixia;Duan Jiang;Li Weiguo;Zhang Aidong
这项工作报告卤代5-（2-羟基苯基）吡唑类pseudilin类似物的潜在目标酶IspD的甲基磷酸（MEP）途径。这种类似物的设计使用的生物电子等排置换的pseudilin核心结构，并通过一个有效的三步路线合成。以AtIspD为基础的筛选和芽前、芽后除草试验表明，这些化合物对AtIspD具有较强的抑制活性，IC 50达3.27 μM，对模式植物油菜和稗草也具有中等至优异的活性。在温室试验中，在150 g/ha的施用率下，三种化合物表现出比伪地灵更高或相当的除草活性。将代表性化合物与AtIspD的变构位点进行分子对接，发现其结合模式类似于伪地林。本工作中建立的生物电子等排和合成方法可作为开发针对MEP途径中IspD的新除草剂和抗菌剂的重要工具。
This work reports halogenated 5-(2-hydroxyphenyl)pyrazoles as pseudilin analogues with the potential to target the enzyme IspD in the methylerythritol phosphate (MEP) pathway. Such analogues were designed using the bioisosteric replacement of the pseudilin core structure and synthesized via an efficient three-step route. WithAtIspD-based screening and pre- and post-emergence herbicidal tests, these compounds were demonstrated to have considerable activities againstAtIspD, with IC50up to 3.27 μM, and against model plants rape and barnyard grass, with moderate to excellent activities. At a rate of 150 g/ha in the greenhouse test, three compounds exhibited higher or comparable herbicidal activities than pseudilin. Molecular docking of representative compounds into the allosteric site ofAtIspD revealed a binding mode similar to that of pseudilin. The established bioisosterism and synthesis method in this work may serve as an important tool for the development of new herbicides and antimicrobials targeting IspD in the MEP pathway.