Anthranilic Diamides Containing Monofluoroalkene Amide Linkers as Potential Insect RyR Activators: Design, Synthesis, Bio-evaluation, and Computational Study

Abstract

In order to develop anthranilic diamides with novel chemotypes, a series of anthranilic diamides with acrylamide linkers were designed and synthesized. The results of preliminary bioassays indicated that compounds with a monofluoroalkene amide linker (Z-isomer) exhibited good larvicidal activity against lepidopteran pests. The LC50 values of compound A23 against Mythimna separata and Plutella xylostella were 1.44 and 3.48 mg·L–1, respectively, while those of chlorantraniliprole were 0.08 and 0.06 mg·L–1, respectively. Compound A23 also exhibited the same level of lethal potency against resistant and susceptible strains of Spodoptera frugiperda at 50 mg·L–1. Compound A23 exhibited similar symptoms as chlorantraniliprole in test larvae. Comparative molecular field analysis was conducted to demonstrate the structure–activity relationship. Central neuron calcium imaging experiments indicated that monofluoroalkene compounds were potential ryanodine receptor (RyR) activators and activated calcium channels in both the endoplasmic reticulum and the cell membrane. Molecular docking suggested that A23 had a better binding potency to P. xylostella RyR than chlorantraniliprole. The MM|GBSA dG bind value of A23 with P. xylostella RyR was 117.611 kcal·mol–1. Monofluoroalkene was introduced into anthranilic diamide insecticides for the first time and brought a novel chemotype for insect RyR activators. The feasibility of fluoroalkenes as insecticide fragments was explored.

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

“…Details of calcium imaging-based studies were described in our reported literature. 29 The neurons used were isolated from M. separata obtained from shallot fields in Tianjin, China. The calcium imaging protocol experiment was referenced from Takahashi's method 40 with improvements.…”

“…These experiments were performed on M. separata neurons. Details of calcium imaging-based studies were described in our reported literature . The neurons used were isolated from M. separata obtained from shallot fields in Tianjin, China.…”

“…28 In our previous work, we designed anthranilic diamide molecules containing a monofluoroalkene amide linker that target the M. separata ryanodine receptor and showed good insecticidal activity against lepidopterous pests (LC 50 = 1.44 mg• L −1 against M. separata, Figure 2B). 29 Motivated by this attempt, we continued to search for new structures of diamide insecticides containing fluoroalkenes. Herein, diamide compounds with monofluoroalkenes were designed by introducing the aliphatic amide and benzene of chlorantraniliprole.…”

“…The monofluoroalkene as bioisostere of an amide offers advantages in lipophilicity, metabolic stability, and target specificity and is already widely applied in the research and development of pharmaceuticals. − Nevertheless, only very recently was monofluoroalkene reported to be used in agrichemicals (Figure A) . In our previous work, we designed anthranilic diamide molecules containing a monofluoroalkene amide linker that target the M. separat a ryanodine receptor and showed good insecticidal activity against lepidopterous pests (LC 50 = 1.44 mg·L –1 against M. separata , Figure B) . Motivated by this attempt, we continued to search for new structures of diamide insecticides containing fluoroalkenes.…”

Design, Synthesis, and Insecticidal Evaluation of N-Pyridylpyrazole Amide Derivatives Containing 4,5-Dihydroisoxazole Amide as Potential Ryanodine Receptor Activators

“…21−23 In the structural modification of CHL (Figure 3A), several literatures mentioned that the N-containing heterocycles were used as bioisosteric substitution of the aliphatic amide moiety (part a), retaining its excellent insecticidal activities against lepidopteran pests such as Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). 12,24−27 In the previous work of our group, 28,29 various diamide derivatives with excellent insecticidal activity have been obtained through innovative modifications of CHL. However, the exploration of Ncontaining heterocycles was not involved.…”