Synthesis and Herbicidal Activity of Triketone-Aminopyridines as Potent p-Hydroxyphenylpyruvate Dioxygenase Inhibitors
Synthesis and Herbicidal Activity of Triketone-Aminopyridines as Potent p-Hydroxyphenylpyruvate Dioxygenase Inhibitors
复制标题
强效对羟基苯丙酮酸双加氧酶抑制剂三酮-氨基吡啶的合成及其除草活性
DOI：
10.1021/acs.jafc.0c07782
复制
发表时间：
2021
影响因子：
6.1
通讯作者：
Yang Guang-Fu
中科院分区：
文献类型：
--
作者：
Nan Jia-Xu;Yang Jing-Fang;Lin Hong-Yan;Yan Yao-Chao;Zhou Shao-Meng;Wei Xue-Fang;Chen Qiong;Yang Wen-Chao;Qu Ren-Yu;Yang Guang-Fu
开发新型的对羟基苯丙酮酸双加氧酶（HPPD）抑制剂已成为除草剂创新最有前途的研究方向之一。1.13.11.27基于我们对开发更强大的HPPD抑制剂的巨大兴趣，我们通过基于结构的药物设计（SBDD）策略设计了一个含苄基的三酮氨基吡啶家族，然后合成了它们。其中活性最好的3-羟基-2-（3，5，6-三氯-4-（（4-异丙基苄基）氨基）吡啶甲酰基）环己-2-烯-1-酮（23，IC_（50）= 0.047 μM）对拟南芥（Arabidopsis thaliana，At）的HPPD活性是市售甲基磺草酮（IC_（50）= 0.273 μM）的5.8倍。预测的对接模型和计算的小分子的关键残基的能量贡献表明，在AtHPPD中检测到与Phe-392的额外的π-π堆积相互作用以及与Met-335和Pro-384的疏水接触，与参比甲基磺草酮相比，最佳活性化合物23的结合。这种分子机制和由此产生的结合亲和力与建议的设计方案和实验值相吻合。值得注意的是，在出苗后处理后，在150 g活性成分（ai）/ha下，除草剂16（3-羟基-2-（3，5，6-三氯-4-（（4-氯苄基）氨基）吡啶甲酰基）环己-2-烯-1-酮）、22（3-羟基-2-（3，5，6-三氯-4-（（4-甲基苄基）氨基）吡啶甲酰基）环己-2-烯-1-酮）和23显示出优异的温室除草效果。化合物16对狗尾草（Setaria viridis）具有上级的防除效果。viridis）与阳性对照甲基磺草酮在多个测试剂量（120、60和30 μ g ai/ha）下的差异。这些结果表明，化合物16作为一种新型的HPPD抑制剂先导化合物，具有很大的应用潜力。绿色的
Exploring novelp-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors has become one of the most promising research directions in herbicide innovation. On the basis of our tremendous interest in exploiting more powerful HPPD inhibitors, we designed a family of benzyl-containing triketone-aminopyridines via a structure-based drug design (SBDD) strategy and then synthesized them. Among these prepared derivatives, the best active 3-hydroxy-2-(3,5,6-trichloro-4-((4-isopropylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one (23, IC50= 0.047 μM) exhibited a 5.8-fold enhancement in inhibitingArabidopsis thaliana(At) HPPD activity over that of commercial mesotrione (IC50= 0.273 μM). The predicted docking models and calculated energy contributions of the key residues for small molecules suggested that an additional π–π stacking interaction with Phe-392 and hydrophobic contacts with Met-335 and Pro-384 were detected inAtHPPD upon the binding of the best active compound23compared with that of the reference mesotrione. Such a molecular mechanism and the resulting binding affinities coincide with the proposed design scheme and experimental values. It is noteworthy that inhibitors16(3-hydroxy-2-(3,5,6-trichloro-4-((4-chlorobenzyl)amino)picolinoyl)cyclohex-2-en-1-one),22(3-hydroxy-2-(3,5,6-trichloro-4-((4-methylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one), and23displayed excellent greenhouse herbicidal effects at 150 g of active ingredient (ai)/ha after postemergence treatment. Furthermore, compound16showed superior weed-controlling efficacy againstSetaria viridis(S. viridis) versus that of the positive control mesotrione at multiple test dosages (120, 60, and 30 g ai/ha). These findings imply that compound16, as a novel lead of HPPD inhibitors, possesses great potential for application in specifically combating the malignant weedS. viridis.