Targeting Voltage-Gated Sodium Channels: Discovery of a Multi-Pest Insecticidal Activity Compound with Negative Cross-Resistance to Pyrethroid Resistance

The resistance to pyrethroid insecticides is becoming increasingly severe, while the number of insecticides with negative cross-resistance (NCR) remains extremely limited. Thus, the development of novel targets and candidate compounds is urgently required. To exploit NCR insecticides targeting the voltage-gated sodium channel (VGSC), structural modifications of the B and C rings were performed on the lead compound 6i, leading to the synthesis of a series of derivatives. Bioassays, electrophysiological experiments and cytotoxicity assays demonstrated that the derivative LC-2 exhibited insecticidal activity against multiple insect pests. Notably, LC-2 showed significant NCR against pyrethroid-resistant Aedes aegypti (resistance ratio = 0.12). Its mode of action involves targeting the insect VGSC and impairing the function of the channel’s fast inactivation gate. Meanwhile, this compound presented low toxicity to mammalian cells. In conclusion, this study identified a novel compound LC-2 with NCR to pyrethroids, multi-pest insecticidal activity, which provides a theoretical basis and material support for insecticide resistance management and the development of low-toxic NCR insecticides.