Discovery of Novel Diamides Scaffold Containing Monofluoro-acrylamides Activating the Insect Ryanodine Receptor

The research and development of organofluorine chemistry has flourished; in particular, monofluoroalkene has aroused considerable interest from medicinal and organic chemists. It is a significant attempt to introduce monofluoroalkene into agrochemicals. In this study, monofluoroalkene was introduced into diamide molecules and inserted between the aliphatic amide and benzene ring, and 44 compounds have been successfully synthesized. The bioassay results showed that compounds with monofluoro-acrylamide moiety (Z-isomers) had excellent larvicidal activity against lepidopteran pests at 5 mg·L^-1. The LC₅₀ values of compounds B16, B18, and B21 against Mythimna separata were 1.02, 1.32, and 0.78 mg·L^-1, respectively. 3D-QSAR analysis including the CoMFA model and the CoMSIA model was conducted to illustrate the contributions of steric, electrostatic, hydrophobic, and hydrogen bond fields on the bioactivity. Moreover, typical symptoms caused by chlorantraniliprole including dehydration, shrinkage, and blackening were also observed on the test larvae treated with monofluoro-acrylamide diamide compounds. M. separata central neurons calcium imaging experiment of compound B18 indicated that the monofluoro-acrylamide diamide compounds were potential insect ryanodine receptor activators. The molecular docking was performed in the CHL binding domain of Plutella xylostella RyR and revealed that the predicted binding mode of compound B21 was slightly different from that of CHL. The MM|GBSA dG Bind values of B21 and CHL with P. xylostella RyR were respectively -85.797 and -95.641 kcal·mol^-1. The present work explored the insecticidal properties of a new diamide scaffold containing a monofluoro-acrylamide fragment and extended the application of monofluoroalkene in the agrochemical field.

3D-QSAR; acrylamide; calcium imaging; diamide insecticide; molecular docking; monofluoroalkene; ryanodine receptor.