Novel Insecticidal Butenolide-Containing Methylxanthine Derivatives: Synthesis, Crystal Structure, Biological Activity Evaluation, DFT Calculation and Molecular Docking.

The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via ¹ H-NMR, ¹³ C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC ₅₀ values of 6.187 mg ⋅ L ^-1 and 3.269 mg ⋅ L ^-1 , respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC ₅₀ =15.743 mg ⋅ L ^-1 ). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compound (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization.
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