Design, synthesis, insecticidal activity, and mechanism of novel diamide derivatives containing acylthiourea targeting insect ryanodine receptors

Abstract

The control of lepidopteran insects poses a significant challenge to the sustainable development of agriculture and forestry. Chlorantraniliprole (CHL), which targets ryanodine receptors (RyRs) in insects, has demonstrated exceptional efficacy in insect management and has thus been extensively utilized. However, the extensive and prolonged application of CHL has led to the rapid development of resistance among insect populations. To mitigate the resistance crisis, 30 novel diamide derivatives containing acylthiourea were designed via structure-based approaches, then virtually screened, synthesized, and characterized. The insecticidal activities against Spodoptera frugiperda (S. frugiperda), Mythinma separata (M. separata), and Plutella xylostella (P. xylostella) showed that most of the target compounds exhibited medium to excellent insecticidal activity. Among them, compounds I-14, I-15, and I-17 had 50%, 37%, and 40% mortality rates against P. xylostella at 0.05 mg L⁻¹, respectively, which were close to that of the positive control CHL (53%). Moreover, the overlap of the 95% confidence interval (CI) values suggested that the efficacy of I-15 was approximately equal to that of CHL. Calcium imaging experiments demonstrated that target compounds acted on S. frugiperda RyRs. The time-lapse [Ca²⁺]_ER measurements verified their safety to nontarget organisms. The binding modes of I-14, I-15, and I-17 with P. xylostella RyRs were predicted using in silico molecular docking analysis. The binding stability was revealed by molecular dynamics simulations. This study provides a valuable reference for the design of RyR-targeting diamide insecticides.