Identification of Isoxazoline Compounds as Potential Insecticidal Agents through High-Throughput Screening and 3D-QSAR Analysis

Plutella xylostella poses a significant global agricultural threat. To identify potential insecticide candidates, we conducted high-throughput screening and constructed three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Screening our in-house isoxazoline database revealed a series of compounds exhibiting insecticidal activity against P. xylostella. Subsequently, a 3D-QSAR model was developed using the screened compounds to facilitate the optimization of compound D36. Bioassays indicated that D36 exhibited superior activity against P. xylostella, with an LC50 value of 0.025 mg/L, surpassing control insecticides indoxacarb (LC50 = 1.45 mg/L), ethiprole (LC50 = 3.81 mg/L), and fluxametamide (LC50 = 0.679 mg/L). Moreover, D36 exhibited LC50 values of 0.934 and 0.601 mg/L against Spodoptera frugiperda and Ostrinia furnacalis, respectively. The results of the density functional theory and molecular docking explain the excellent activity of D36. Additionally, transcriptomic analysis, enzyme-linked immunosorbent assay, and molecular docking studies suggested that D36 may affect the central nervous system of target insects and interact with GABA receptors. These results highlight the potential of D36 as a novel isoxazoline candidate for the effective control of P. xylostella and other Lepidoptera pests.