基于 3D-QSAR 的分子设计发现超高活性 N-苯基吡唑作为候选杀虫剂,Journal of Agricultural and Food Chemistry

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基于 3D-QSAR 的分子设计发现超高活性 N-苯基吡唑作为候选杀虫剂
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-03-01 , DOI: 10.1021/acs.jafc.2c08719
Jinzhou Ren _{1,

2,

3} , Xia Ji _{1,

2,

3} , Wei Gao _{1,

2,

3} , Zhenwu Yu _{1,

2,

3} , Kun Li _{1,

2,

3} , Lixia Xiong _{1,

2,

3} , Na Yang _{1,

2,

3} , Yuxin Li _{1,

2,

3} , Zhengming Li _{1,

2,

3} , Zhijin Fan _{1,

2,

3}

Affiliation

三维定量构效关系（3D-QSAR）是指导新农药开发中分子设计的最重要和最有效的工具之一。Chlorantraniliprole 是一种邻氨基苯甲酸二酰胺兰尼碱受体 (RyR) 激动剂，具有超高活性、高选择性和哺乳动物安全性。为了继续我们对新杀虫剂开发的研究，在这里，我们以氯虫苯甲酰胺类似物的 3D-QSAR 为指导，设计了新的杀虫剂N-苯基吡唑。大多数合成的目标化合物对Mythimna separata、Plutella xylostella和Spodoptera frugiperda表现出中等到极好的活性。化合物III b和III y对M. separata显示出与氯虫苯甲酰胺相似的活性（LC ₅₀值：分别为 0.21、0.25 和 0.16 μg mL ^–1）。化合物III b对小菜蛾的效力比氯虫苯甲酰胺高 3 倍。对于S. frugiperda ， III a和III b的效力分别比阳性对照高 2.9 和 2.0 倍。标题化合物的作用方式通过钙成像实验和使用其目标 RyR 的分子对接得到验证。III b可以很好地与突变的小菜蛾对接RyRs，这意味着与商业 RyR 激动剂相比，潜在的交叉耐药风险较低。密度泛函理论计算表明结构修饰具有更高效力的可行性。化合物III b被发现是一种超高活性杀虫剂候选物，具有广谱的害虫综合治理。

"点击查看英文标题和摘要"

3D-QSAR-Based Molecular Design to Discover Ultrahigh Active N-Phenylpyrazoles as Insecticide Candidates

Three-dimensional quantitative structure–activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III b and III y showed similar activity against M. separata as chlorantraniliprole (LC₅₀ values: 0.21, 0.25, and 0.16 μg mL^–1 respectively). Compounds III b exhibited a 3-fold higher potency against P. xylostella than chlorantraniliprole. For S. frugiperda, the potency of III a and III b was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III b can dock well with mutated P. xylostella RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III b was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.

更新日期：2023-03-01

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