Development of S-Fluxametamide for Bioactivity Improvement and Risk Reduction: Systemic Evaluation of the Novel Insecticide Fluxametamide at the Enantiomeric Level

Abstract

Increasing numbers of novel pesticides have been applied in agriculture. However, traditional evaluation of pesticides does not distinguish between their enantiomers, which may lead to inaccurate results. In this study, systematic research on the chiral insecticide fluxametamide was conducted at the enantiomeric level. The methods for enantioseparation and semipreparative separation of fluxametamide enantiomers were developed. The optical rotation and absolute configuration of two enantiomers were determined, and their stability was verified in solvents and soils. Enantioselective bioactivities against four target pests (Plutella xylostella, Spodoptera exigua, Aphis gossypii, and Tetranychus cinnabarinus) were tested. Acute toxicities of fluxametamide enantiomers toward honeybees were also evaluated. S-(+)-Isomer exhibited 52.1–304.4 times and 2.5–3.7 times higher bioactivity than R-(−)-isomer and rac-fluxametamide, respectively. Meanwhile, rac-fluxametamide was more toxic than S/R-isomer, and S-(+)-isomer showed >30-fold higher acute toxicity than R-(−)-isomer. Molecular docking studies were performed with γ-aminobutyric acid receptor (GABAR) to monitor the mechanism of stereoselective bioactivity. The better Grid score of S-(+)-fluxametamide (−60.12 kcal/mol) than R-(−)-enantiomer (−56.59 kcal/mol) indicated higher bioactivity of S-(+)-isomer than of R-(−)-isomer. The dissipation of fluxametamide in cabbage, Chinese cabbage, and soil was nonenantioselective under field conditions. Development of S-(+)-fluxametamide could maintain the high-efficacy and low-risk properties, which should attract attention of producers, applicators, and managers of pesticides.

Enantioseparation and dissipation monitoring of oxathiapiprolin in grape using supercritical fluid chromatography tandem mass spectrometry

“…Usually, the enantiomers have the same physical and chemical properties but often have different bioactivity, toxicity, and environmental behavior [8]. For instance, the bioactivity of (+)‐ S ‐fluxametamide was 52.1−304.4 times higher than (−)‐ R ‐fluxametamide and the toxicity was more than 30‐fold relative to R ‐(−)‐isomer [9]. However, no enantioselective dissipation of fluxametamide was observed in cabbage and soil under field conditions [9].…”

“…For instance, the bioactivity of (+)‐ S ‐fluxametamide was 52.1−304.4 times higher than (−)‐ R ‐fluxametamide and the toxicity was more than 30‐fold relative to R ‐(−)‐isomer [9]. However, no enantioselective dissipation of fluxametamide was observed in cabbage and soil under field conditions [9]. Similarly, difenoconazole contains two chiral centers and have four stereoisomers; stereoselective study indicated the (2 S ,4 S )‐difenoconazole showed the highest toxicity, lowest bioactivity, and least enrichment in tomato and cucumber [10].…”

Status and outlook for acaricide and insecticide discovery

“…The acute toxicity of fluxametamide enantiomers toward honey bees has been evaluated. Its S ‐( + ) ‐ isomer exhibited 52.1–304.4 and 2.5–3.7 times higher bioactivity than the R‐ (−) ‐ isomer and rac‐ fluxametamide, respectively 23 . The S‐ (+) ‐ isomer showed more than 30‐fold higher acute toxicity than the R‐ (−)‐isomer.…”

“…Its S-(+)-isomer exhibited 52.1-304.4 and 2.5-3.7 times higher bioactivity than the R-(−)-isomer and rac-fluxametamide, respectively. 23 The S-(+)-isomer showed more than 30-fold higher acute toxicity than the R-(−)-isomer. Molecular docking studies have been performed with GABA receptor to monitor the mechanism of stereoselective bioactivity.…”

“…The S‐ (+) ‐ isomer showed more than 30‐fold higher acute toxicity than the R‐ (−)‐isomer. Molecular docking studies have been performed with GABA receptor to monitor the mechanism of stereoselective bioactivity 23 . The separated R‐ (−)‐isomer of fluxametamide may not be completely insecticidal inactive, but it demonstrates insufficient field performance.…”