From Proline to\nChlorantraniliprole Mimics: Computer-Aided\nDesign, Simple Preparation, and Excellent Insecticidal Profiles

Chlorantraniliprole (CHL), a favored agricultural insecticide,\nis renowned for its high efficiency and broad-spectrum effectiveness\nagainst lepidoptera insects. However, the urgency for new insecticide\ndevelopment is underscored by the intricate multistep preparation\nprocess and modest overall yields of CHL, along with the escalating\nchallenge of insect resistance. In response, we have crafted CHL mimics\nfrom proline employing computer-aided drug design. Molecular docking\nanalysis of CHL’s interactions with the ryanodine receptor\n(RyR) revealed that the nitrogen atom within the pyrazole moiety does\nnot engage in pivotal interactions. Its removal may not abolish bioactivity\nentirely but could substantially simplify the synthetic process, thereby\nenhancing atom economy. This revelation prompted the exclusion of\nnitrogen and the subsequent formation of a pyrrole ring, enabling\nthe meticulous design of synthetic pathways characterized by cost-effective\nprecursors, streamlined synthesis, the avoidance of toxic reagents,\nminimal instrumentation, and high yields in the pursuit of innovative\nRyR modulators. Among these modulators, <b>A</b><sub><b>1</b></sub> and <b>B</b><sub><b>1</b></sub>, obtained with\nyields exceeding 60%, showcased exceptional insecticidal potency,\nwith LC<sub>50</sub> values spanning from 0.12 to 1.47 mg L<sup>–1</sup> against P. xylostella and M. separate. The inhibitory effects of these two\ncompounds on insect detoxification enzymes imply a reduced likelihood\nof eliciting resistance in comparison to CHL, a finding further corroborated\nby their insecticidal potency against resistant pests. Moreover, molecular\ndocking, MD simulations, and DFT calculations provided valuable structural\ninsights, potentially unraveling the superior insecticidal activity\nof these two molecules, and thus paving the way for developing more\npotent insecticides.