Development of Novel α-Santonin-Based Oxazole Derivatives as Potential Insecticide Candidates

The natural product α-santonin was first used as an anthelmintic agent for animals and human beings with remarkable therapeutic effects; however, there are fewer reports and applications on its structural optimization and derivatives in the field of agrochemicals. Here, we designed and synthesized a series of novel α-santonin-based oxazole derivatives, evaluated their insecticidal activities against common pests, including Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus, and preliminarily explored the insecticidal mechanism. It was found that VII14 exhibited the strongest GI activity against M. separata, with the final corrected mortality rate of 96.3%, which was 2.6 times higher than that of the positive control toosendanin. Compounds VII2, VII5, VII13, VII14, and VII16 exhibited more promising aphicidal activity against M. persicae with LD₅₀ values of 0.021, 0.021, 0.023, 0.020, and 0.022 μg/larvae, respectively, superior to rotenone (0.024 μg/larvae). Moreover, more than half of the α-santonin-based oxazole derivatives exhibited potent larvicidal activity against P. xylostella. Especially, VII19 and VII20 had LC₅₀ values of 0.47 and 0.54 mg/mL, respectively, which were significantly higher than that of rotenone (0.86 mg/mL). What is more, the control efficacy assay under greenhouse conditions further demonstrated that VII19 and VII20 displayed potent insecticidal activity. Preliminary mechanistic studies indicated that VII19 had significant inhibitory effects on glutathione S-transferase (GST) in P. xylostella, and molecular docking further verified that there were multiple sites and types of interactions between VII19 and GST, thus exerting insecticidal activity. Additionally, the potent derivatives showed good safety against nontarget aquatic organisms. This study will provide insights for the further development of α-santonin-based derivatives as highly efficient and low-toxicity green insecticide candidates.