Discovery of natural product‐derived pesticide candidates: synthesis, aphicidal activity, and toxicological evaluation of andrographolide derivatives

BACKGROUND: To address pest resistance, environmental concerns, and non-target toxicity associated with conventional pesticides, the natural product andrographolide was structurally optimized for the development of eco-friendly insecticides. RESULTS: , representing a 16-fold enhancement over the parent compound. In greenhouse pot experiments, 9i achieved a control efficacy 4.7 times greater than that of andrographolide. Structure-activity relationship analysis indicated that introducing aromatic substituents containing electron-withdrawing groups at the C3 position significantly improved insecticidal activity. Morphological observations by stereomicroscopy and scanning electron microscopy revealed severe damage to the insect body surface after treatment. Biochemical assays further showed that 9i markedly induced the activities of key antioxidant enzymes, including superoxide dismutase and catalase. Toxicological evaluation demonstrated favorable selectivity, with low toxicity toward non-target organisms, including honeybees, mammalian bEND.3 cells, zebrafish larvae, and representative microorganisms. CONCLUSION: Structural optimization substantially enhances the insecticidal activity of andrographolide. Compound 9i represents a promising lead candidate for eco-friendly insecticide development and provides a valuable basis for future pesticide discovery. © 2026 Society of Chemical Industry.