Design, Synthesis, and Insecticidal Activity of Sulfonamide Structures Containing Methoxyamine as Potential Inhibitors of V‐ATPase

Pesticides that act on unique targets are favored in pesticide research because of their unique mechanism of action and lower proneness to developing cross-resistance. In the previous work, the natural product cingulin V, which was isolated from Celastrus angulatus Maxim in our laboratory, was determined to act on the subunit H on V-ATPase. After homology modeling and virtual docking of the subunit H on V-ATPase, the highest scoring compound was selected for structural modification; two critical functional groups-the sulfonamide and propargyloxy moieties-were ultimately identified as being essential for the significant enhancement of insecticidal activity. On the basis of the previous work, to investigate whether the introduction of oxygen atoms into the sulfonamide structure can enhance the compound's biological activity, we synthesized 25 sulfonamide derivatives and evaluated their insecticidal activity against Mythimna separata. Bioassay results demonstrated that methoxyamine-substituted compounds exhibited significant efficacy at 0.5 mg/mL. Notably, compound 5.3 showed activity with an LC₅₀ of 0.131 mg/mL, representing a 200-fold potency enhancement over celangulin V and a 5.26-fold improvement compared to the lead compound. Compound 5.3 was verified to act on ATPase as well through symptomological analysis and molecular docking. This study provided potential inhibitors of V-ATPase for the M. separata control.