Synthesis and Biological Evaluation of Oxime Ether Derivatives as Potential Pesticide Candidates by the Scaffold Hopping Strategy

Scaffold hopping has emerged as a powerful strategy for innovating and optimizing lead compounds in agrochemical research. To develop insecticides with enhanced efficacy, we implemented this approach to structurally refine novel oxime ether derivatives identified in our previous work. In this paper, 68 novel oxime derivatives spanning 12 structural series were designed, synthesized, and evaluated against Mythimna separata, Plutella xylostella, and Aedes aegypti. Notably, derivatives from Series 10–12, designed through a ring-opening strategy, demonstrated superior bioactivity. Compound 10h achieved an LC₅₀ value of 0.108 mg/mL against M. separata, and compound 12p exhibited exceptional potency against P. xylostella (LC₅₀ = 0.027 mg/mL), both significantly outperforming the original lead compound celangulin V. Detailed transmission electron microscopy observations revealed severe midgut structural damage in treated insects, confirming their stomach poisoning mechanism. Overall, this work validates scaffold hopping as an effective optimization strategy and provides new insights for agrochemical lead development.