Design, Synthesis, Antifeedant Activity, and Mechanistic Research of Aconitine Derivatives

For decades, natural product-derived insect repellents have been a major focus of research. Aconitine, a diterpene alkaloid isolated from Aconitum plants, exhibits not only significant antifeedant activity but also potent toxicological effects against certain insects. In this study, 48 novel aconitine derivatives were synthesized via esterification of the C3-hydroxyl group. Among them, compound A4 demonstrated optimum antifeedant activity with an AFC₅₀ value of 4.91 µg/cm², surpassing that of the parent compound aconitine (AFC₅₀ = 11.65 µg/cm²) and the positive control Azadirachtin (AFC₅₀ = 5.57 µg/cm²). Meanwhile, compound A10 exhibited the strongest cytotoxicity (IR = 84.71%, IC₅₀ = 31.51 µM), comparable to the positive control chlorfenapyr (IR = 88%, IC₅₀ = 3.53 µM). Structure-activity relationship analysis revealed that medium-length aliphatic chains (C5-C8), electron-withdrawing groups at the para position of benzene ring, and heterocyclic substituents could significantly enhance the antifeedant activity. Cytotoxicity assays and morphological observations indicated typical apoptotic characteristics, which were further confirmed by fluorescence staining and flow cytometry. Thus, this study suggests that the synthesized derivatives possess promising development as advanced insect repellents. This work provides a new structural framework for the development of potent, natural product-based insect antifeedants and offers insights into their potential mode of action.