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<p>The sucking pests such as aphids, planthoppers, and whiteflies pose a significant threat to global crop productivity, causing estimated losses of up to 40% in affected areas. Reports indicate that resistance to traditional agents such as imidacloprid has increased by more than 50% over the last decade, underscoring the urgency for innovative solutions. Neonicotinoids, which target insect nicotinic acetylcholine receptors (nAChRs), remain a vital component of pest management, offering an important alternative. Flupyrimin, a pyridylamide-type neonicotinoid with a unique mode of action on insect nAChRs, exhibits strong efficacy against resistant pest populations. In this study, a synthetic route to Flupyrimin was established, and the design and preparation of ten structural analogs were carried out. In these analogs, the trifluoroacetyl group was replaced by pyridylcarbamoyl moieties, and the pyridine ring was further derivatized. The synthetic strategy utilizes mild, non-hazardous solvents and high-efficiency reaction conditions, thus providing a practical and scalable approach for the generation of this novel class of compounds. Bioassays against <i>Lipaphis erysimi</i> (200&#xa0;mg/L) demonstrated that compounds <b>IIIa</b> and <b>IIIc</b> exhibited mortality rates in excess of 45%, while <b>IIIb</b> exhibited a mortality rate that exceeded 65% mortality. Molecular docking simulation indicated that <b>IIIb</b> exhibited the strongest binding to insect nAChRs, supported by favorable hydrogen-bonding and π-π interactions. Conversely, fluorine substitution at the 3-position in <b>IIIc</b> resulted in a slight deviation in binding orientation and a reduction in affinity. Furthermore, the larger chlorine atom in <b>IIId</b> introduced steric hindrance that prevented optimal binding. Single-crystal X-ray analysis of <b>IIIe</b> confirmed its structure and conformation. These results suggest that pyridylamide-based neonicotinoids may serve as a valuable scaffold for the development of next-generation insecticidal agents. The distinct structural features of these receptors are distinct, and their predicted binding modes suggest the potential for different receptor interactions. This has the potential to provide avenues for future resistance-management strategies.</p>

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Design, synthesis, and biological evaluation of pyridylamide-type neonicotinoid derivatives based on flupyrimin scaffold

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Qingwen Fang,
  • Ying Wen,
  • Jie Wang,
  • Xuliang Nie,
  • Yueming Xu,
  • Guozheng Huang,
  • W. W. W. W. Kandegama,
  • Shangxing Chen,
  • Yong Ye,
  • Dayong Peng

摘要

The sucking pests such as aphids, planthoppers, and whiteflies pose a significant threat to global crop productivity, causing estimated losses of up to 40% in affected areas. Reports indicate that resistance to traditional agents such as imidacloprid has increased by more than 50% over the last decade, underscoring the urgency for innovative solutions. Neonicotinoids, which target insect nicotinic acetylcholine receptors (nAChRs), remain a vital component of pest management, offering an important alternative. Flupyrimin, a pyridylamide-type neonicotinoid with a unique mode of action on insect nAChRs, exhibits strong efficacy against resistant pest populations. In this study, a synthetic route to Flupyrimin was established, and the design and preparation of ten structural analogs were carried out. In these analogs, the trifluoroacetyl group was replaced by pyridylcarbamoyl moieties, and the pyridine ring was further derivatized. The synthetic strategy utilizes mild, non-hazardous solvents and high-efficiency reaction conditions, thus providing a practical and scalable approach for the generation of this novel class of compounds. Bioassays against Lipaphis erysimi (200 mg/L) demonstrated that compounds IIIa and IIIc exhibited mortality rates in excess of 45%, while IIIb exhibited a mortality rate that exceeded 65% mortality. Molecular docking simulation indicated that IIIb exhibited the strongest binding to insect nAChRs, supported by favorable hydrogen-bonding and π-π interactions. Conversely, fluorine substitution at the 3-position in IIIc resulted in a slight deviation in binding orientation and a reduction in affinity. Furthermore, the larger chlorine atom in IIId introduced steric hindrance that prevented optimal binding. Single-crystal X-ray analysis of IIIe confirmed its structure and conformation. These results suggest that pyridylamide-based neonicotinoids may serve as a valuable scaffold for the development of next-generation insecticidal agents. The distinct structural features of these receptors are distinct, and their predicted binding modes suggest the potential for different receptor interactions. This has the potential to provide avenues for future resistance-management strategies.