Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor,Journal of Agricultural and Food Chemistry

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Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-05-04 , DOI: 10.1021/acs.jafc.3c09157
Bai-Feng Zheng ₁ , Yang Zuo ₁ , Wen-Yi Yang ₁ , Hui Liu ₁ , Qiong-You Wu ₁ , Guang-Fu Yang ₁

Affiliation

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4) plays a pivotal role in chlorophyll biosynthesis in plants, making it a prime target for herbicide development. In this study, we conducted an investigation aimed at discovering PPO-inhibiting herbicides. Through this endeavor, we successfully identified a series of novel compounds based on the pyridazinone scaffold. Following structural optimization and biological assessment, compound 10ae, known as ethyl 3-((6-fluoro-5-(6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate, emerged as a standout performer. It exhibited robust activity against Nicotiana tabacum PPO (NtPPO) with an inhibition constant (K_i) value of 0.0338 μM. Concurrently, we employed molecular simulations to obtain further insight into the binding mechanism with NtPPO. Additionally, another compound, namely, ethyl 2-((6-fluoro-5-(5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate (10bh), demonstrated broad-spectrum and highly effective herbicidal properties against all six tested weeds (Leaf mustard, Chickweed, Chenopodium serotinum, Alopecurus aequalis, Poa annua, and Polypogon fugax) at the dosage of 150 g a.i./ha through postemergence application in a greenhouse. This work identified a novel lead compound (10bh) that showed good activity in vitro and excellent herbicidal activity in vivo and had promising prospects as a new PPO-inhibiting herbicide lead.

中文翻译：

作为新型原卟啉原 IX 氧化酶抑制剂的含哒嗪酮衍生物的设计、合成和生物学评价

原卟啉原 IX 氧化酶（PPO，EC 1.3.3.4）在植物叶绿素生物合成中发挥着关键作用，使其成为除草剂开发的主要目标。在这项研究中，我们进行了一项旨在发现 PPO 抑制性除草剂的调查。通过这一努力，我们成功鉴定了一系列基于哒嗪酮支架的新型化合物。经过结构优化和生物学评估，化合物10ae ，称为乙基3-((6-氟-5-(6-氧代-4-(三氟甲基)哒嗪-1(6 H )-基)苯并[ d ]噻唑-2) -基）硫代）丙酸酯，表现出色。它对烟草PPO ( Nt PPO) 表现出强大的活性，抑制常数 ( K _i ) 值为 0.0338 μM。同时，我们采用分子模拟来进一步了解Nt PPO 的结合机制。另外，另一种化合物，即乙基2-((6-氟-5-(5-甲基-6-氧代-4-(三氟甲基)哒嗪-1( 6H )-基)苯并[ d ]噻唑-2-)基）硫代）丙酸酯（ 10bh ），在 150 g ai/ 的剂量下，对所有六种测试杂草（芥菜、繁缕、藜、看麦穗、早熟禾和毛蓼）表现出广谱和高效的除草特性。 ha 通过在温室中进行芽后施用。这项工作鉴定了一种新型先导化合物（ 10bh ），该化合物表现出良好的体外活性和优异的体内除草活性，作为新型 PPO 抑制性除草剂先导化合物具有广阔的前景。

更新日期：2024-05-04

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