Design, Synthesis, and Evaluation of Novel Isoxazoline Derivatives as Potent GABA Receptor Modulators

The current economic globalization is inextricably linked to the process of agricultural globalization, and the development of efficient and green pesticides is particularly crucial to this process. In this work, a series of isoxazoline derivatives targeting the γ-aminobutyric acid (GABA) receptors of lepidopteran insects were designed, utilizing the CoMFA model to guide the splicing of bioactive fragments. Subsequently, these novel compounds were synthesized, characterized, and evaluated. The majority of the compounds showed moderate to good activity against Mythimna separata (M. separata), Plutella xylostella (P. xylostella), and Spodoptera frugiperda (S. frugiperda). Among them, compound C-29 (LC₅₀ = 0.002 mg/L) exhibited more than 5-fold higher potency than fluxametamide (LC₅₀ = 0.011 mg/L) against P. xylostella. Meanwhile, compound C-35 (LC₅₀ = 0.032 mg/L, 0.025 mg/L) exhibited 2.5-fold and 7.5-fold higher potencies than fluxametamide (LC₅₀ = 0.080, 0.188 mg/L) against M. separata and S. frugiperda. Notably, the LC₅₀ values for bee toxicity were 16.887 μg/bee (C-35), 0.055 μg/bee (fluralaner), and 1.567 μg/bee (fluxametamide), demonstrating that C-35 exhibited 307.0-fold and 10.8-fold lower toxicity to Apis mellifera than fluralaner and fluxametamide, respectively. In addition, the impacts of compounds C-32 and C-35 on the GABAergic signaling pathway in S. frugiperda were examined through HPLC and gene ontology (GO) enrichment analysis. Molecular docking and molecular dynamics simulations further elucidated the differences in the binding modes and interaction relationships between the highly active molecules and fluralaner. This work provides new scientific ideas for the development of a highly efficient and environmentally friendly novel neurotransmitter modulator.