新型 1,2,3-苯并三嗪-4-酮衍生物作为有效的 4-羟基苯丙酮酸双加氧酶抑制剂的药效导向发现,Journal of Agricultural and Food Chemistry

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新型 1,2,3-苯并三嗪-4-酮衍生物作为有效的 4-羟基苯丙酮酸双加氧酶抑制剂的药效导向发现
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2022-05-26 , DOI: 10.1021/acs.jafc.2c01507
Yao-Chao Yan ₁ , Wei Wu ₁ , Guang-Yi Huang ₁ , Wen-Chao Yang ₁ , Qiong Chen ₁ , Ren-Yu Qu ₁ , Hong-Yan Lin ₁ , Guang-Fu Yang ₁

Affiliation

4-羟基苯丙酮酸双加氧酶 (HPPD) 是一种功能性蛋白质，几乎存在于所有需氧生物中。在农药领域，HPPD因其在植物中独特的生物功能，被公认为是目前除草剂的重要靶点之一。在 Auto Core Fragment in silico Screening (ACFIS) 网络服务器中，通过药效团关联片段虚拟筛选 (PFVS) 方法筛选出具有 1,2,3-benzotriazine-4-one 的潜在 HPPD 抑制剂。分子模拟研究推动了“hit-to-lead”优化过程，合成了 1,2,3-benzotriazine-4-one 衍生物家族。因此，6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-5-methyl-3-(2-methylbenzyl)benzo[ d ][1,2,3]triazin-4(3 H）-一（15bu ) 被确定为1,2,3-benzotriazine-4-one 衍生物中最好的 HPPD 抑制剂 (IC _{50 = 36 nM)，与阳性对照甲基磺草酮 (IC}₅₀ = 289 纳米）。At HPPD -15bu复合物的晶体学信息揭示了与靶蛋白结合的配体的几个重要相互作用，即三酮基序与At HPPD的金属离子的二齿螯合相互作用，由,2,3-benzotriazine-4-one 部分和 Phe-424 和 Phe-381 的两个苯环，以及由邻-CH组成的多向疏水接触_{核心支架的3-}苄基和一些疏水残基。此外，化合物15bu在测试剂量下对五种目标杂草表现出 100% 的抑制作用，这与甲基磺草酮的杂草防治效果相当。总的来说，融合的 1,2,3-benzotriazine-4-one-triketone 杂化物是一种有前途的化学工具，可用于开发更有效的 HPPD 抑制剂，并为除草剂创新提供有价值的先导化合物15bu。

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Pharmacophore-Oriented Discovery of Novel 1,2,3-Benzotriazine-4-one Derivatives as Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a functional protein existing in almost all aerobic organisms. In the field of agricultural chemicals, HPPD is acknowledged to be one of the crucial targets for herbicides at present due to its unique bio-function in plants. In the Auto Core Fragment in silico Screening (ACFIS) web server, a potential HPPD inhibitor featuring 1,2,3-benzotriazine-4-one was screened out via a pharmacophore-linked fragment virtual screening (PFVS) method. Molecular simulation studies drove the process of “hit-to-lead” optimization, and a family of 1,2,3-benzotriazine-4-one derivatives was synthesized. Consequently, 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-5-methyl-3-(2-methylbenzyl)benzo[d][1,2,3]triazin-4(3H)-one (15bu) was identified to be the best HPPD inhibitor (IC₅₀ = 36 nM) among the 1,2,3-benzotriazine-4-one derivatives, which had over 8-fold improvement of enzyme inhibition compared with the positive control mesotrione (IC₅₀ = 289 nM). Crystallography information for the AtHPPD–15bu complex revealed several important interactions of the ligand bound upon the target protein, i.e., the bidentate chelating interaction of the triketone motif with the metal ion of AtHPPD, a tight π–π stacking interaction consisting of the1,2,3-benzotriazine-4-one moiety and two benzene rings of Phe-424 and Phe-381, and the polydirectional hydrophobic contacts consisting of the ortho-CH₃-benzyl group of the core scaffold and some hydrophobic residues. Furthermore, compound 15bu displayed 100% inhibition against the five species of target weeds at the tested dosage, which was comparable to the weed control of mesotrione. Collectively, the fused 1,2,3-benzotriazine-4-one-triketone hybrid is a promising chemical tool for the development of more potent HPPD inhibitors and provides a valuable lead compound 15bu for herbicide innovation.

更新日期：2022-05-26

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