Design, synthesis, and insecticidal activity evaluation of PROTACs based on the structure of chlorantraniliprole

As a cutting-edge approach in biomedicine, proteolysis-targeting chimeras (PROTACs) technology eliminates target proteins through an event driven degradation mode. Its high selectivity and unique mechanism have made it a research hotspot in medicine, agrochemistry, and other fields. In this study, PROTACs were leveraged to conjugate chlorantraniliprole and pomalidomide via alkyl chains or polyethylene glycol chains to constructeight novel PROTACs molecules targeting the ryanodine receptor (RyR). Biological activity assays showed that the target compounds exhibited good insecticidal activity against the Lepidopteran pests Plutella xylostella and Mythimna separata, with the lethality both exceeding 80% at the concentration of 50 mg/L. Among them, LC₅₀ values of 0.50 μmol/L for compound A8 against Plutella xylostella and 1.13 μmol/L for A5 against Mythimna separata, representing 5.6-fold and 28-fold reductions in potency compared to chlorantraniliprole, respectively. Western blot analysis indicated that none of the compounds induced RyR degradation, potentially due to insufficient ligand binding affinity or inefficient ubiquitin transfer. Subsequent optimization should focus on E3 ligase ligands and linker structures. This work lays a foundation for applying PROTACs technology to pesticide development.