Design, synthesis, and biological activity of novel isoxazoline-thiazole derivatives as potential insecticides

Isoxazolines, which act as modulators of the GABA receptor (GABAR), are significant agrochemicals for controlling of resistant pest populations. However, their sustainable application is often hindered by toxicity to beneficial non-target organisms, particularly pollinators. To investigate the potential for reducing the toxicity of isoxazoline analogs to honeybees, a series of novel isoxazoline-thiazole derivatives were designed and synthesized using the "ring-closure" strategy. Bioassays demonstrated that these compounds retained promising insecticidal activity. Among them, compounds 9m and 9l exhibited excellent insecticidal activity against Spodoptera litura, with LC₅₀ values of 0.87 and 0.80 mg/L, respectively, comparable to that of fluxametamide (0.65 mg/L). Moreover, compound 9m also showed good insecticidal activity against Plutella xylostella. Importantly, compound 9m displayed reduced acute toxicity to honeybees, with an LD₅₀ of 8.98 μg/bee (indicating moderate toxicity), whereas fluxametamide has an LD₅₀ of 1.24 μg/bee (indicating high toxicity). Integrated molecular docking, MD simulations, and DFT calculations suggested that the incorporation of the thiazole moiety contributed to favorable target binding while diminishing interactions with honeybee GABAR. In conclusion, these isoxazoline-thiazole derivatives may serve as potential candidates and lead structures for the development of novel insecticides with low toxicity to honeybees.