Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
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作为 4-羟基苯基丙酮酸双加氧酶抑制剂的新型吡唑-喹唑啉-2,4-二酮杂化物的发现
DOI：
10.1021/acs.jafc.0c00051
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发表时间：
2020-05-06
影响因子：
6.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
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作者：
He, Bo;Wu, Feng-Xu;Yang, Guang-Fu
4-羟苯基丙酮酸双加氧酶（HPPD，EC 1.13.11.27）已被鉴定为用于抗性杂草控制的除草剂发现中最重要的靶标之一。在继续努力发现有效的新HPPD抑制剂，我们采用了扩环策略，设计了一系列新的吡唑-喹唑啉-2，4-二酮杂合物的基础上先前发现的吡唑-异吲哚啉-1，3-二酮支架。一种化合物，3-（2-氯苯基）-6-（5-羟基-1，3-二甲基-1H-吡唑-4-羰基）1，5-二甲基喹唑啉-2，4（1H，3 H）-二酮（9 bj）对AtHPPD显示出优异的效力，IC 50值为84 nM，其效力比磺酰吡唑（IC 50 = 1359 nM）高约16倍，比甲基磺草酮（IC 50 = 226 nM）高2.7倍。此外，以1.75埃的分辨率确定AtHPPD-9 bj复合物（PDB ID 6LGT）的共晶结构。与现有的HPH）抑制剂类似，化合物9 bj与金属离子形成双齿螯合相互作用，与Phe 381和Phe 424形成π-π堆积相互作用。与此相反，具有双重构象的喹唑啉-2，4-二酮的N3位的邻氯苯基被疏水残基（Met 335、Leu 368、Leu 427、Phe 424、Phe 392和Phe 381）包围。值得注意的是，温室测定表明，大多数化合物在150 g活性成分（ai）/ha的施用率下对至少一种测试杂草显示出优异的除草活性（完全抑制）。最有希望的是，化合物9aj和9 bi在150 g ai/ha的剂量下不仅表现出显著的广谱杂草防治效果，而且对棉花、花生和玉米显示出非常好的作物安全性。
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonyl)1,5-dimethylquinazoline-2,4(1H,3H)-dione (9bj), displayed excellent potency against AtHPPD, with an IC50 value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC50 = 1359 nM) and 2.7-fold more potent than mesotrione (IC50 = 226 nM). Furthermore, the co-crystal structure of the AtHPPD-9bj complex (PDB ID 6LGT) was determined at a resolution of 1.75 angstrom. Similar to the existing HPPD inhibitors, compound 9bj formed a bidentate chelating interaction with the metal ion and a pi-pi stacking interaction with Phe381 and Phe424. In contrast, o-chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds 9aj and 9bi not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.