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 <i>Mythimna separata</i> Walker, <i>Myzus persicae</i> Sulzer, and <i>Plutella xylostella</i> Linnaeus, and preliminarily explored the insecticidal mechanism. It was found that <b>VII14</b> exhibited the strongest GI activity against <i>M. separata</i>, with the final corrected mortality rate of 96.3%, which was 2.6 times higher than that of the positive control toosendanin. Compounds <b>VII2</b>, <b>VII5</b>, <b>VII13</b>, <b>VII14</b>, and <b>VII16</b> exhibited more promising aphicidal activity against <i>M. persicae</i> 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 <i>P. xylostella</i>. Especially, <b>VII19</b> and <b>VII20</b> 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 <b>VII19</b> and <b>VII20</b> displayed potent insecticidal activity. Preliminary mechanistic studies indicated that <b>VII19</b> had significant inhibitory effects on glutathione <i>S-</i>transferase (GST) in <i>P. xylostella</i>, and molecular docking further verified that there were multiple sites and types of interactions between <b>VII19</b> 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.