The mode of action of isocycloseram: A novel isoxazoline insecticide

Blythe, Judith; Earley, Fergus G.P.; Piekarska-Hack, Katarzyna; Firth, Lucy C.; Bristow, Julia; Hirst, Elizabeth A.; Goodchild, James A.; Hillesheim, Elke; Crossthwaite, Andrew J.

doi:10.1016/j.pestbp.2022.105217

Cited by 21 publications

(17 citation statements)

References 46 publications

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“…The binding site of novel RDL GABA receptor allosteric modulators like broflanilide and isocycloseram was shown to be distinct from that of NCAs. 21,22 Based on mutation analysis and computational modeling, M3-M1 interfaces between two adjacent subunits is highly likely to be their binding pocket. 21,22 Interestingly, we found that the A2 0 N heterozygous mutants exhibit increased sensitivity to broflanilide but resistance to isocycloseram, suggesting that these two insecticides may share similar yet nonoverlapping binding sites.…”

Section: Discussionmentioning

confidence: 99%

Functional validation of A2′N mutation of the RDL GABA receptor against fipronil via molecular modeling and genome engineering in drosophila

Qiao,

Zhou,

Zhang

et al. 2023

Pest Management Science

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BACKGROUNDInsect RDL (resistant to dieldrin) receptors are essential pentameric ligand‐gated chloride channels that mediate the neuroinhibitory effect of GABA, the chief inhibitory neurotransmitter in the central nervous system. These receptors serve as primary targets for various insecticides, including noncompetitive antagonists (NCAs) such as cyclodiene organochlorines and phenylpyrazoles, as well as allosteric modulators like meta‐diamides and isoxazolines. This study focuses on a newly discovered A2′N mutation within the RDL receptors, identified in fipronil‐resistant planthoppers. Despite in vitro electrophysiological studies have proposed its role in conferring target‐site resistance, in vivo genetic functional validation of this mutation remains unexplored.RESULTSOur research employed toxicity bioassays, assessing various Rdl genotypes against a spectrum of insecticides, including fipronil, α‐endosulfan, broflanilide, and isocycloseram. Results revealed distinct resistance profiles for A2′N and A2′S mutants, indicating different binding interactions of RDL receptors with NCAs. Significantly, the A2′N heterozygote showed substantial resistance to fipronil, despite its homozygous lethality. Molecular modeling and docking simulations further supported these findings, highlighting unique binding poses for fipronil and α‐endosulfan.CONCLUSIONThis study confirmed that A2′N mutation of the RDL GABA receptor confer high resistance to fipronil in vivo. The observed resistance in A2′N mutants is likely attributable to a steric hindrance mechanism, wherein the introduction of larger side chains hampers fipronil binding, even in a heterozygous state. © 2023 Society of Chemical Industry.

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Section: Discussionmentioning

confidence: 99%

Functional validation of A2′N mutation of the RDL GABA receptor against fipronil via molecular modeling and genome engineering in drosophila

Qiao,

Zhou,

Zhang

et al. 2023

Pest Management Science

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“…Rdl A301S is derived from Rdl MDRR (RRID:BDSC_1675), an Rdl allele isolated from a natural population in Maryland 28 , and underwent isogenization and selection on dieldrin to eliminate the metabolic resistance and maintain the dieldrin target site resistance 29 . The Rdl MDRR was obtained from the Bloomington Drosophila Stock Center.…”

Section: Methodsmentioning

confidence: 99%

A reductionist paradigm for high-throughput behavioural fingerprinting inDrosophila melanogaster

Jones

Willis

Firth

et al. 2022

Preprint

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Understanding how the brain encodes behaviour is the ultimate goal of neuroscience and the ability to objectively and reproducibly describe and quantify behaviour is a necessary milestone on this path. Recent progresses in machine learning and computational power have pushed the development and adoption of powerful systems leveraging on high-resolution videorecording to track pose and describe behaviour in all four dimensions, however the temporal and spatial resolution of these systems come as a compromise with their throughput and accessibility. Here we describe coccinella, an open source reductionist framework that allows for high-throughput analysis of behaviour using real-time tracking on a distributed mesh of microcomputers followed by resource-lean statistical learning. We show that a reductionist system outperforms state-of-the-art alternatives when exploring the pharmacobehaviour in Drosophila melanogaster.

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“…Among them, the GABA-gated chloride channel allosteric modulators are new integrated pest management tools, , including isoxazoline insecticides and meta-diamide insecticides, which were in group 30 by the Insecticide Resistance Action Committee (IRAC) . So far, many isoxazoline insecticides have been discovered, such as fluralaner, fluxametamide, afoxolaner, isocycloseram, sarolaner, and lotilaner . These isoxazoline insecticides had similar structures and mode of action, which not only prevent and control some pests resistant to insecticides but also have excellent effects on a variety of parasites.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif

Zhong,

Sun,

Han

et al. 2023

J. Agric. Food Chem.

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It is important to develop new insecticides with a new mode of action because of increasing pesticide resistance. In this study, a series of novel aryl isoxazoline derivatives containing the pyrazole-5-carboxamide motif were designed and synthesized. Their structures were confirmed by 1 H NMR, 13 C NMR, and HRMS. Bioassays indicated that the 24 compounds synthesized possessed excellent insecticidal activity against Mythimna separate and no activity against Aphis craccivora and Tetranychus cinnabarinus. Among these aryl isoxazoline derivatives, 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrozol-3-yl)-N-(4fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (IA-8) had the best insecticidal activity against M. separate, which is comparable with the positive control fluralaner. The molecular docking results of compound IA-8 and fluralaner with the GABA model demonstrated the same docking mode between compound IA-8 and positive control fluralaner in the active site of GABA. Molecular structure comparisons and ADMET analysis can potentially be used to design more active compounds. The structure−activity relationships are also discussed. This work provided an excellent insecticide for further optimization.

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The mode of action of isocycloseram: A novel isoxazoline insecticide

Cited by 21 publications

References 46 publications

Functional validation of A2′N mutation of the RDL GABA receptor against fipronil via molecular modeling and genome engineering in drosophila

Functional validation of A2′N mutation of the RDL GABA receptor against fipronil via molecular modeling and genome engineering in drosophila

A reductionist paradigm for high-throughput behavioural fingerprinting inDrosophila melanogaster

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif

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