RESUMEN
The ryanodine receptor (RyR) is an intracellular calcium channel critical to the regulation of insect muscle contraction and the target site of diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide. To-date, diamides are the only known class of synthetic molecules with high potency against insect RyRs. Target-based screening of an informer library led to discovery of a novel class of RyR activators, pyrrole-2-carboxamides. Efforts to optimize receptor activity resulted in analogs with potency comparable to that of commercial diamides when tested against RyR of the fruit fly, Drosophila melanogaster. Surprisingly, testing of pyrrole-2-carboxamides in whole-insect screens showed poor insecticidal activity, which is partially attributed to differential selectivity among insect receptors and rapid detoxification. Among various lepidopteran species field resistance to diamide insecticides has been well documented and in many cases has been attributed to a single point mutation, G4946E, of the RyR gene. As with diamide insecticides, the G4946E mutation confers greatly reduced sensitivity to pyrrole-2-carboxamides. This, coupled with findings from radioligand binding studies, indicates a shared binding domain between anthranilic diamides and pyrrole-2-carboxamides.
Asunto(s)
Insecticidas , Mariposas Nocturnas , Animales , Drosophila melanogaster/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Resistencia a los Insecticidas , Insecticidas/toxicidad , Mariposas Nocturnas/metabolismo , Pirroles/toxicidad , Rianodina , Canal Liberador de Calcio Receptor de Rianodina/genética , ortoaminobenzoatos/toxicidadRESUMEN
N-Substituted amino-2(5H)-oxazolones A are a novel class of insecticides acting as nicotinic acetylcholine receptor (nAChR) agonists and show potent activity against hemipteran insect species. Here we report the discovery and preparation of this class of chemistry. Our efforts in SAR elucidation, biological activity evaluation, as well as mode-of-action studies are also presented.
Asunto(s)
Insectos/efectos de los fármacos , Insecticidas/química , Oxazolona/química , Aminación , Animales , Insectos/fisiología , Insecticidas/toxicidad , Oxazolona/toxicidad , Receptores Nicotínicos/metabolismoRESUMEN
Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide range of pests from multiple insect orders. Here we report on the chemistry, biology and structure-activity trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial development.
Asunto(s)
Canales de Calcio/química , Insecticidas/química , Pirazoles/química , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , ortoaminobenzoatos/química , Animales , Áfidos , Insecticidas/síntesis química , Lepidópteros , Estructura Molecular , Pirazoles/síntesis química , Canal Liberador de Calcio Receptor de Rianodina/química , Relación Estructura-Actividad , ortoaminobenzoatos/síntesis químicaRESUMEN
Isoxazoline insecticides have been shown to be potent blockers of insect GABA receptors with excellent activity on a broad pest range, including Lepidoptera and Hemiptera. Herein we report on the synthesis, biological activity and mode-of-action for a class of 4-heterocyclic aryl isoxazoline insecticides.
Asunto(s)
Canales de Cloruro/antagonistas & inhibidores , Insecticidas/farmacología , Isoxazoles/farmacología , Receptores de GABA/metabolismo , Animales , Canales de Cloruro/metabolismo , Relación Dosis-Respuesta a Droga , Insectos , Insecticidas/síntesis química , Insecticidas/química , Isoxazoles/síntesis química , Isoxazoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: As the world population grows towards 9 billion by 2050, it is projected that food production will need to increase by 60%. A critical part of this growth includes the safe and effective use of insecticides to reduce the estimated 20-49% loss of global crop yields owing to pests. The development of new insecticides will help to sustain this protection and overcome insecticide resistance. RESULTS: A novel class of mesoionic compounds has been discovered, with exceptional insecticidal activity on a range of Hemiptera and Lepidoptera. These compounds bind to the orthosteric site of the nicotinic acetylcholine receptor and result in a highly potent inhibitory action at the receptor with minimal agonism. The synthesis, biological activity, optimization and mode of action will be discussed. CONCLUSION: Triflumezopyrim insect control will provide a powerful tool for control of hopper species in rice throughout Asia. Dicloromezotiaz can provide a useful control tool for lepidopteran pests, with an underexploited mode of action among these pests. © 2016 Society of Chemical Industry.
Asunto(s)
Hemípteros/efectos de los fármacos , Insecticidas/farmacología , Mariposas Nocturnas/efectos de los fármacos , Periplaneta/efectos de los fármacos , Animales , Áfidos/efectos de los fármacos , Áfidos/crecimiento & desarrollo , Hemípteros/crecimiento & desarrollo , Proteínas de Insectos/metabolismo , Insecticidas/síntesis química , Mariposas Nocturnas/crecimiento & desarrollo , Antagonistas Nicotínicos/metabolismo , Periplaneta/crecimiento & desarrolloRESUMEN
Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace (3)H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 µM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick ß2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism. Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid.
Asunto(s)
Áfidos/efectos de los fármacos , Insecticidas/farmacología , Antagonistas Nicotínicos/metabolismo , Periplaneta/efectos de los fármacos , Piridinas/farmacología , Pirimidinonas/farmacología , Xenopus laevis/metabolismo , Animales , Áfidos/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Periplaneta/fisiologíaRESUMEN
Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 µg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.
Asunto(s)
Antiparasitarios/farmacología , Canales de Cloruro/metabolismo , Isoxazoles/farmacología , Naftalenos/farmacología , Siphonaptera/efectos de los fármacos , Garrapatas/efectos de los fármacos , Animales , Antiparasitarios/sangre , Antiparasitarios/farmacocinética , Antiparasitarios/uso terapéutico , Cucarachas/efectos de los fármacos , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/fisiopatología , Perros , Drosophila melanogaster/efectos de los fármacos , Fenómenos Electrofisiológicos/efectos de los fármacos , Femenino , Infestaciones por Pulgas/tratamiento farmacológico , Infestaciones por Pulgas/prevención & control , Infestaciones por Pulgas/veterinaria , Isoxazoles/sangre , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Masculino , Naftalenos/sangre , Naftalenos/farmacocinética , Naftalenos/uso terapéutico , Oocitos/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Distribución Aleatoria , Infestaciones por Garrapatas/tratamiento farmacológico , Infestaciones por Garrapatas/prevención & control , Infestaciones por Garrapatas/veterinaria , Xenopus laevisRESUMEN
Anthranilic diamides, which include the new commercial insecticide, chlorantraniliprole, are an exciting new class of chemistry that target insect ryanodine receptors. These receptors regulate release of stored intracellular calcium and play a critical role in muscle contraction. As with insects, nematodes express ryanodine receptors and are sensitive to the plant alkaloid, ryanodine. However the plant parasitic nematode, Meloidogyne incognita, is insensitive to anthranilic diamides. Expression of a full-length Drosophila melanogaster ryanodine receptor in an insect cell line confers sensitivity to the receptor agents, caffeine and ryanodine along with nanomolar sensitivity to anthranilic diamides. Replacement of a 46 amino acid segment in a highly divergent region of the Drosophila C-terminus with that from Meloidogyne results in a functional RyR which lack sensitivity to diamide insecticides. These findings indicate that this region is critical to diamide sensitivity in insect ryanodine receptors. Furthermore, this region may contribute to our understanding of the differential selectivity diamides exhibit for insect over mammalian ryanodine receptors.
Asunto(s)
Diamida/toxicidad , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Insecticidas/toxicidad , Canal Liberador de Calcio Receptor de Rianodina/química , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Línea Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/química , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Proteínas del Helminto/química , Proteínas del Helminto/genética , Proteínas del Helminto/metabolismo , Datos de Secuencia Molecular , Canal Liberador de Calcio Receptor de Rianodina/genética , Alineación de Secuencia , Tylenchoidea/química , Tylenchoidea/efectos de los fármacos , Tylenchoidea/genética , Tylenchoidea/metabolismoRESUMEN
Rynaxypyr is a highly potent and selective activator of insect ryanodine receptors with exceptional activity on a broad range of Lepidoptera. A strong correlation between insecticidal activity and ryanodine receptor activation is observed along with selective activity against insect over mammalian receptors. The synthesis and biological results are presented.
Asunto(s)
Insecticidas/farmacología , Lepidópteros/efectos de los fármacos , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , ortoaminobenzoatos/farmacología , Animales , Línea Celular , Humanos , Insecticidas/síntesis química , Insecticidas/química , Lepidópteros/citología , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad , Pruebas de Toxicidad Aguda , Regulación hacia Arriba/efectos de los fármacos , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/químicaRESUMEN
Bridged-tricyclic cyanoguanidines 1 were found to be active as insecticides. The preparation and structure-activity relationships of oxacyclic (X=O) and carbocyclic (X=CH(2)) analogues of 1 is described. Compounds 1 were found to inhibit acetylcholinesterase with IC(50) values comparable to the organophosphate Paraoxon. Unlike organophosphates, cyanoguanidines 1 were shown to reversibly bind acetylcholinesterase. This mode of action is shared by the structurally-related natural product Huperzine A.