Application of Natural Sesquiterpene Lactone for Pesticide Discovery: Design, Synthesis, and Insecticidal Evaluation of Xanthatin Derivatives Featuring Isoxazoline, Arylvinyl, and Sulfone Motifs

Xanthatin, a natural sesquiterpene lactone, served as an agrochemical scaffold to develop three series of derivatives bearing isoxazoline, arylvinyl, and sulfone motifs in this work. Bioassays identified compounds IIa, IId, IIh, and IIIa as highly potent against prethird-instar larvae of Mythimna separata, exhibiting 3.9–4.5-fold greater insecticidal efficacy than xanthatin and inducing typical neurotoxic symptoms. In greenhouse trials, compound IIh (500 mg/L for 72 h) achieved 81.7% corrected mortality and 79.9% leaf protection against M. separata, highlighting its practical potential. These derivatives also showed significant oral toxicity against prethird-instar larvae of Plutella xylostella . Notably, they exhibited Reduced cytotoxicity toward the human keratinocyte cell line (HaCaT) relative to xanthatin indicated enhanced dermal safety profile. Combined enzyme assays and molecular docking identified acetylcholinesterase (AChE) as the primary target. These novel xanthatin-derived compounds offer high insecticidal potency and favorable safety profile, representing promising agrochemical candidates.