Improving Insecticidal Activity of Chlorantraniliprole by Replacing the Chloropyridinyl Moiety with a Substituted Cyanophenyl Group

Insect ryanodine receptors (RyRs) are molecular targets of the anthranilic diamide insecticides. In the present study, a new series of anthranilic diamides containing a cyanophenyl pyrazole moiety were rationally designed by active-fragment assembly and computer-aided design using the 3D structure of Plutella xylostella RyRs as a receptor and chlorantraniliprole as a ligand. Most of the titled compounds showed good toxicity against Mythimna separate, P. xylostella, and Spodoptera frugiperda. Compounds CN06, CN11, and CN16 with corresponding LC50 values of 0.15, 0.29, and 0.52 mg-L-1, respectively, against M. separate showed comparable activity to that of chlorantraniliprole (0.13 mg-L-1). Surprisingly, CN06, CN11, and CN16 with corresponding LC50 values of 1.6 x 10(-5), 3.0 x 10(-5), and 2.8 x 10(-5) mg-L-1, respectively, against P. xylostella were at least 5-fold more active than chlorantraniliprole (1.5 x 10(-4) mg-L-1). In the case of S. frugiperda, CN06, CN11, and CN16 had good potency but lower than chlorantraniliprole in terms of LC(50 )values (0.58, 0.54, and 0.56 mg-L-1 versus 0.31 mg-L-1). Molecular docking of CN06 and chlorantraniliprole to P. xylostella RyRs validated the molecular design, and the calcium imaging technique further proved the potential target of CN06 as RyRs. Compounds CN06, CN11, and CN16 could be more effective than chlorantraniliprole in targeting the resistant RyR mutants of S. frugiperda (G4891E, I4734M) through the binding mode and energy obtained by molecular docking. Density functional theory calculations (DFT) and electrostatic potential (ESP) studies gave the structure-activity relationship. Compounds CN06, CN11, and CN16 could be used as potent insecticide leads for further optimization.

Automated summary

In this study, a series of anthranilic diamide compounds were designed and synthesized for their insecticidal activity. These compounds showed good toxicity against several insect species, including some that were more active than the commonly used chlorantraniliprole. Molecular docking and calcium imaging experiments provided evidence for the potential target of these compounds as RyRs. The results suggest that these compounds could be promising leads for the development of more effective insecticides.