RESUMO
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.
Assuntos
Inseticidas , Mariposas , Animais , Drosophila melanogaster/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Resistência a Inseticidas , Inseticidas/toxicidade , Mariposas/metabolismo , Pirróis/toxicidade , Rianodina , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , ortoaminobenzoatos/toxicidadeRESUMO
Insecticide resistance has been and continues to be a significant problem for invertebrate pest control. As such, effective insecticide resistance management (IRM) is critical to maintain the efficacy of current and future insecticides. A technical group within CropLife International, the Insecticide Resistance Action Committee (IRAC) was established 35 years ago (1984) as an international association of crop protection companies that today spans the globe. IRAC's focus is on preserving the long-term utility of insect, mite, and most recently nematode control products through effective resistance management to promote sustainable agriculture and improved public health. A central task of IRAC has been the continual development and documentation of the Mode of Action (MoA) Classification scheme, which serves as an important tool for implementing IRM strategies focused on compound rotation / alternations. Updates to the IRAC MoA Classification scheme provide the latest information on the MoA of current and new insecticides and acaricides, and now includes information on biologics and nematicides. Details for these new changes and additions are reviewed herein.
Assuntos
Produtos Biológicos , Inseticidas , Animais , Antinematódeos , Insetos , Resistência a InseticidasRESUMO
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program which led to the discovery of triflumezopyrim as a highly potent insecticide controlling various hopper species. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.
Assuntos
Descoberta de Drogas , Inseticidas/farmacologia , Ortópteros/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinonas/farmacologia , Animais , Relação Dose-Resposta a Droga , Inseticidas/química , Estrutura Molecular , Piridinas/química , Pirimidinonas/química , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Fluazaindolizine is a new highly effective and selective product for the control of plant parasitic nematodes. Specificity for nematodes coupled with absence of activity against the target sites of commercial nematicides suggests that fluazaindolizine has a novel mode of action. The discovery, structure-activity development and biological properties for this new class of nematicides are presented.
Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Indolizinas/farmacologia , Praguicidas/farmacologia , Sulfonamidas/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Produtos Agrícolas/parasitologia , Drosophila melanogaster/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Indolizinas/síntese química , Indolizinas/toxicidade , Praguicidas/síntese química , Praguicidas/toxicidade , Raízes de Plantas/parasitologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade , Tylenchoidea/efeitos dos fármacosRESUMO
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program that led to the identification of dicloromezotiaz as a potent insecticide to control a broad range of lepidoptera. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.
Assuntos
Lepidópteros/efeitos dos fármacos , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Inseticidas/química , Inseticidas/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores Nicotínicos/química , Relação Estrutura-AtividadeRESUMO
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure-activity relationship elucidation and biological activity evaluation are also presented.
Assuntos
Inseticidas/química , Inseticidas/toxicidade , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/toxicidade , Pirimidinonas/química , Pirimidinonas/toxicidade , Animais , Hemípteros/efeitos dos fármacos , Hemípteros/fisiologia , Proteínas de Insetos/metabolismo , Lepidópteros/efeitos dos fármacos , Lepidópteros/fisiologia , Receptores Nicotínicos/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel class of synthetic tubulin polymerization disruptors, based on a substituted pyrazin-2-one core, has been discovered. These molecules have proven to be potent broad spectrum fungicides, with activity on agriculturally important ascomycete and basidiomycete pathogens. They have also been found to be particularly potent against human rhabdomyosarcoma cells. Using an efficient synthetic route, the agricultural and medicinal activity was explored.
Assuntos
Antineoplásicos/farmacologia , Fungicidas Industriais/farmacologia , Pirazinas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungicidas Industriais/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazinas/química , Relação Estrutura-AtividadeAssuntos
Complicações na Gravidez , Anormalidades da Pele , Extremidades , Fazendeiros , Feminino , Humanos , Gravidez , Prurido/diagnósticoRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Patients with non-alcoholic steatohepatitis (NASH) have increased plasmatic and hepatic concentrations of bile acids (BA), suggesting that they can be associated with the progression of the disease. Hepatic nuclear receptors are known to modulate genes controlling BA metabolism; thus, in this work we aimed to compare the expression of liver nuclear receptors -farnesoid X (FXR), small heterodimer partner (SHP) and liver X alpha (LXRα) receptors- and BA transporters -sodium+/taurocholate cotransporting polypeptide (NTCP) and bile salt export pump (BSEP)- in liver biopsy samples of patients with simple steatosis (SS) and NASH. MATERIAL AND METHODS: Forty patients with biopsy-proven NALFD were enrolled between 2009 and 2012; liver biopsies were classified as SS (N = 20) or NASH (N = 20) according to the NAFLD activity score. Gene expression of nuclear FXR, LXRα, SHP, NTCP and BSEP was analyzed by real-time reverse transcription polymerase chain reaction and protein level was quantified by western blot. RESULTS: Gene expression of FXR, SHP, NTCP and BSEP was significantly up-regulated in the NASH group in comparison with SS patients (P < 0.05). In contrast, protein level for FXR, SHP and NTCP was decreased in the NASH patients vs. the SS group (P < 0.05). Gene and protein profile of LXRα did not show differences between groups. CONCLUSIONS: The results suggest that liver nuclear receptors (FXR and SHP) and BA transporters (NTCP and BSEP) are associated with the progression of NAFLD.
Assuntos
Transportadores de Cassetes de Ligação de ATP/análise , Fígado/química , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Nucleares Órfãos/análise , Receptores Citoplasmáticos e Nucleares/análise , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Biópsia , Western Blotting , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Fígado/patologia , Receptores X do Fígado , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Receptores Nucleares Órfãos/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Citoplasmáticos e Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Membro 3 da Família 12 de Carreador de Soluto/análise , Membro 3 da Família 12 de Carreador de Soluto/genética , Regulação para CimaRESUMO
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.
Assuntos
Insetos/efeitos dos fármacos , Inseticidas/química , Oxazolona/química , Aminação , Animais , Insetos/fisiologia , Inseticidas/toxicidade , Oxazolona/toxicidade , Receptores Nicotínicos/metabolismoRESUMO
Big torque inputs in controls could increase energy consumption, and big estimated perturbations in observers could produce device damages. Therefore, it would be interesting to propose a constrained control for safe reference tracking and a constrained observer for safe perturbation estimation in robots. Furthermore, the best gains in controls produce a balance between safe reference tracking and save energy consumption. Therefore, it would be interesting to propose a method to find the best gains. In this paper, an observer-based differential evolution constrained control is proposed for safe reference tracking in robots. The contributions are described as follows: (1) a constrained observer is proposed for safe perturbation estimation in robots, (2) a constrained control is proposed for safe reference tracking in robots, (3) a differential evolution optimizer is used to find the best gains in an observer-based constrained control, (4) the robust stability in an observer-based constrained control is assured, (5) the pseudo-code of an observer-based differential evolution constrained control is detailed. The proposed observer-based differential evolution constrained control is applied for safe reference tracking in two robots.
Assuntos
Redes Neurais de Computação , Robótica , Algoritmos , Humanos , TorqueRESUMO
In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides. Evaluation of such 2-(pyridin-3-yl)-2H-indazole carboxamides revealed that even analogs containing only simple alkyl amides attached at the 4 or 5 positions possess promising insecticidal activity. Extensive optimization of this novel class of 2-(pyridin-3-yl)-2H-indazole carboxamides led to identifying indazapyroxamet for commercial development. © 2024 Society of Chemical Industry.
RESUMO
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.
Assuntos
Canais de Cálcio/química , Inseticidas/química , Pirazóis/química , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ortoaminobenzoatos/química , Animais , Afídeos , Inseticidas/síntese química , Lepidópteros , Estrutura Molecular , Pirazóis/síntese química , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese químicaRESUMO
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.
Assuntos
Canais de Cloreto/antagonistas & inibidores , Inseticidas/farmacologia , Isoxazóis/farmacologia , Receptores de GABA/metabolismo , Animais , Canais de Cloreto/metabolismo , Relação Dose-Resposta a Droga , Insetos , Inseticidas/síntese química , Inseticidas/química , Isoxazóis/síntese química , Isoxazóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Insects of the order Lepidoptera are among the most destructive global pests, causing billions of dollars in damage annually. A new class of N-arylpyrazole-4-methylpiperidines with potent activity on lepidopteran species has been discovered. RESULTS: In a high-throughput insecticide screen compound 1 was identified to possess modest activity on the lepidopteran insect Plutella xylostella. Optimization of 1 to compound 42 resulted in a compound with excellent activity on Spodoptera exigua, Spodoptera frugiperda, and Helicoverpa zea with median lethal concentrations values of 2.8, 1.4, and 12.5 ppm respectively. Although the mode of action remains unknown, these compounds do not appear to work by many of the known biochemical mechanisms of insect control. CONCLUSION: N-Arylpyrazole-4-methylpiperidines represent a new class of insecticides with excellent activity on a broad spectrum of lepidopteran pests. Studies to date indicate the potential for a novel mode of action; however, the target site is unknown at present. © 2023 Society of Chemical Industry.
Assuntos
Inseticidas , Mariposas , Animais , Inseticidas/farmacologia , Pirazóis/farmacologia , Insetos , Controle de Insetos/métodos , Spodoptera , LarvaRESUMO
PURPOSE: To evaluate in vivo parameters as biomarkers of limbal stem cell function and to establish an objective system that detects and stage limbal stem cell deficiency (LSCD). METHODS: A total of 126 patients (172 eyes) with LSCD and 67 normal subjects (99 eyes) were included in this observational cross-sectional comparative study. Slit-lamp biomicroscopy, in vivo laser scanning confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT) were performed to obtain the following: clinical score, cell morphology score, basal cell density (BCD), central corneal epithelial thickness (CET), limbal epithelial thickness (LET), total corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and tortuosity coefficient. Their potential correlations with the severity of LSCD were investigated, and cutoff values were determined. RESULTS: An increase clinical score correlated with a decrease in central cornea BCD, limbal BCD, CET, mean LET, maximum LET, CNFL, CNFD, CNBD, and tortuosity coefficient. Regression analyses showed that central cornea BCD, CET and CNFL were the best parameters to differentiate LSCD from normal eyes (Coef = 3.123, 3.379, and 2.223; all p < 0.05). The rank correlation analysis showed a similar outcome between the clinical scores and the central cornea BCD (ρ = 0.79), CET (ρ = 0.82), and CNFL (ρ = 0.71). A comprehensive LSCD grading formula based on a combination of these parameters was established. CONCLUSIONS: A comprehensive staging system combining clinical presentation, central cornea BCD, CET, and CNFL is established to accurately and objectively diagnose LSCD and stage its severity.
Assuntos
Doenças da Córnea , Limbo da Córnea , Doenças da Esclera , Biomarcadores , Córnea/inervação , Doenças da Córnea/diagnóstico , Estudos Transversais , Humanos , Microscopia Confocal/métodos , Células-TroncoRESUMO
PURPOSE: The purpose of this study was to evaluate the expression of cytokeratin (K) 13 on the corneal surface and to validate its application in the diagnosis of limbal stem cell deficiency (LSCD). METHODS: This prospective comparative study included 26 corneal impression cytology (IC) specimens from patients diagnosed with LSCD. Twenty-three IC specimens from normal donors served as controls. K12 and K13 expression were detected on the IC specimens by immunohistochemistry study. The number of K12 + or K13 + cells in all areas of the IC was quantified using ImageJ software. RESULTS: The epithelial cells harvested from IC specimens from control corneas were all K12 + . In eyes with LSCD, K13 + and K12 + /K13 + cells accounted for 93.8% and 2.6%, respectively, in the cornea. In eyes with sectoral LSCD, the median number of K13 + cells in the clinically affected area was higher than that in the unaffected area (810.0 vs. 115.0 cells/mm 2 ; P < 0.001). No significant correlation was found between the LSCD severity and the number of K12 + cells (r = -0.284, P = 0.16) or K13 + cells (r = -0.011, P = 0.95). The presence of at least 16 K13 + cells/mm 2 was suggestive of LSCD. CONCLUSIONS: Identification of K13 + cells on IC specimens provides a simple and reliable method to detect conjunctival epithelial cells on the cornea. K13 is a marker for diagnosing LSCD and localizing the involved area in sectoral LSCD.
Assuntos
Doenças da Córnea , Epitélio Corneano , Limbo da Córnea , Doenças da Esclera , Biomarcadores/metabolismo , Doenças da Córnea/diagnóstico , Doenças da Córnea/metabolismo , Epitélio Corneano/metabolismo , Humanos , Queratina-13/metabolismo , Estudos Prospectivos , Células-Tronco/metabolismoRESUMO
OBJECTIVE: Using anterior segment optical coherence tomography (AS-OCT), we investigated the epithelial thickness (ET) of the central cornea and limbal regions in patients with limbal stem cell deficiency (LSCD) as a diagnostic and staging parameter. DESIGN: Prospective, cross-sectional study. METHODS: The central corneal epithelium thickness (CET) and maximum limbal epithelium thickness (mLET) were measured in the superior, inferior, nasal, and temporal limbus on AS-OCT images of the normal and eyes with LSCD. CET was obtained by 1-point (OCT-CET1) and 3-point measurement (OCT-CET3). The values of OCT-CET1 and OCT-CET3 were compared to the CET obtained with in vivo confocal microscopy (IVCM-CET). RESULTS: Sixty-eight eyes of 50 patients with LSCD and 52 eyes of 34 normal subjects were included. The mean (±standard deviation) OCT-CET3 was 55.0 ± 3.0 µm (range, 50.6-62.0 µm) in the control group and 41.6 ± 10.8 µm (range, 0-56.3 µm) in the LSCD group (P < .001). OCT-CET3 had a better correlation with IVCM-CET (r = 0.91) than did OCT-CET1 (r = 0.87, P = .001). The degree of reduction in OCT-CET3 increased in more advanced clinical stages of LSCD (all P < .001). The OCT-CET3 cutoff value that suggests LSCD was 46.6 µm. Compared with the control group, the LSCD group had decreases in mLET in all 4 limbal regions (all P < .001). The sensitivity and specificity of OCT-CET3 is the highest among all mLET in detecting LSCD. CONCLUSIONS: Both CET and mLET were thinner in patients with LSCD than in normal subjects. OCT-CET3 appears to be a reliable parameter to confirm LSCD when there is clinical suspicion.
Assuntos
Doenças da Córnea/diagnóstico , Epitélio Corneano/patologia , Limbo da Córnea/patologia , Células-Tronco/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Epitélio Corneano/diagnóstico por imagem , Feminino , Análise de Fourier , Humanos , Limbo da Córnea/diagnóstico por imagem , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos Prospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
Diamide insecticides have emerged as one of the most promising new classes of insecticide chemistry owing to their excellent insecticidal efficacy and high margins of mammalian safety. Chlorantraniliprole and flubendiamide, the first two insecticides from this class, demonstrate exceptional activity across a broad range of pests in the order Lepidoptera. This chemistry has been confirmed to control insects via activation of ryanodine receptors which leads to uncontrolled calcium release in muscle. The high levels of mammalian safety are attributed to a strong selectivity for insect over mammalian receptors.