Discovery of Novel Meta-Diamide Derivatives with Improved Safety as GABA Receptor-Targeted Insecticides by the Scaffold-Hopping Strategy and 3D-QSAR Models

Abstract The extensive application of meta-diamide insecticides has raised serious concerns regarding their toxicity to aquatic nontarget organisms, necessitating the development of safer alternatives. In this study, a combined in silico approach integrating a scaffold-hopping strategy and three-dimensional quantitative structure–activity relationship (3D-QSAR) models was employed to discover novel meta-diamide derivatives as GABA receptor-targeted insecticides with improved safety profiles. Reliable 3D-QSAR models were constructed based on meta-diamide derivatives developed through a scaffold-hopping strategy, which ultimately enabled the design and synthesis of the novel compound A31. The bioassay results showed that compound A31 displayed good insecticidal activity against Plutella xylostella, with an LC50 value of 0.13 mg/L, and it demonstrated greater safety for zebrafish. Molecular docking studies confirmed that compound A31 maintained favorable binding modes within the GABA receptor. These findings provide valuable insights into the rational design of environmentally compatible meta-diamide insecticides and offer promising candidates for further experimental validation.