Studies on the Design, Synthesis, and Insecticidal Activity Evaluation of New Caffeine-Acrylate Derivatives as Potential Ryanodine Receptor Activators

On the basis of insecticidal leading structures of methylxanthine-acrylates I and II, a series of new caffeine-acrylate derivatives A-F were designed and synthesized via various structural optimization strategies. The structures of new compounds were confirmed through ¹H NMR, ¹⁹F NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). The bioassays showed that some of the new ester compounds possessed high insecticidal potentials against Plutella xylostellaL. and Mythimna separata Walker with improved insecticidal activity compared to the lead compounds. Notably, new compounds B8, B10, C1, C3, C5, and E2, which demonstrated promising insecticidal activity, merit further in-depth exploration in the future. The structure-activity relationships of these compounds were analyzed and discussed in detail. The calcium imaging experiment revealed that representative compound C3 could activate the release of calcium ions in insect neuron cells, suggesting that this type of compound is a potential ryanodine receptor (RyRs) activator. In addition, molecular docking simulations were employed to predict the binding mode between C3 and RyRs. The results in this study provide useful information for the discovery and development of new methylxanthine natural product-based pesticides.