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1.
J Agric Food Chem ; 67(45): 12538-12546, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31638796

RESUMO

Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds (4 and 6) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Compounds 4 and 6 showed potent inhibition against Escherichia coli PDHc-E1 (IC50 = 4.13-23.76 µM) and also strong algicidal activities against Synechocystis sp. PCC 6803 (EC50 = 1.7-8.1 µM) and Microcystis sp. FACHB905 (EC50 = 2.1-11.8 µM). In particular, the algicidal activities of 6d against four algal species were not only higher than that of prometryn; they were also comparable to or higher than that of copper sulfate. The analogues 4c, 4d, 6d, and 6e displayed potent algicidal activities and inhibition of E. coli PDHc-E1 but exhibited negligible inhibition of porcine PDHc-E1. As revealed by molecular docking, site-directed mutagenesis, enzymatic assays, and an inhibition kinetic analysis, 4c and 6d inhibited PDHc-E1 in a competitive manner. Our results suggest that highly selective, effective algicides can be developed by rationally designing competitive PDHc-E1 inhibitors.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Microcystis/efeitos dos fármacos , Pirimidinas/farmacologia , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Synechocystis/efeitos dos fármacos , Triazóis/farmacologia , Proteínas de Bactérias/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Cinética , Microcystis/química , Microcystis/enzimologia , Simulação de Acoplamento Molecular , Pirimidinas/química , Piruvato Desidrogenase (Lipoamida)/química , Relação Estrutura-Atividade , Synechocystis/química , Synechocystis/enzimologia , Triazóis/química
2.
J Agric Food Chem ; 67(38): 10782-10790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31490683

RESUMO

Systematic investigation of cyproconazole, including absolute stereochemistry, fungicidal activity, quantification in two matrixes, and stereoselective degradation in cucumber, are conducted in this study. By virtue of vibrational circular dichroism (VCD) spectroscopy, absolute configurations of four stereoisomers were identified to be (2R,3R)-(+)-, (2R,3S)-(+)-, (2S,3S)-(-)-, and (2S,3R)-(-)-cyproconazoles. Then four stereoisomers exhibited stereoselective fungicidal activities against Fusarium graminearum Schw and Magnaporthe oryzae, and the order of fungicidal activity was (2S,3S)-(-)-stereoisomer > the stereoisomer mixture > (2S,3R)-(-)-stereoisomer > (2R,3R)-(+)-stereoisomer > (2R,3S)-(+)-stereoisomer. Moreover, chiral liquid chromatography-tandem mass spectrometry was used to identify and quantify cyproconazole stereoisomers in soil and cucumber matrixes. Good linearity (R2 ≥ 0.99) and recoveries (86.79-92.47%, RSD ≤ 3.94%) for them were achieved, individually. Furthermore, stereoselective degradation of four cyproconazole stereoisomers was observed in cucumber and the order of degradation rate was (2R,3R)-(+)-cyproconazole > (2S,3S)-(-)-cyproconazole > (2R,3S)-(+)-cyproconazole > (2S,3R)-(-)-cyproconazole. We envision that such systematic assessments of chiral fungicides at an enantiomeric level would provide valuable information in future studies involving enantioselective physiological, metabolic, and toxicological activities.


Assuntos
Fungicidas Industriais/química , Triazóis/química , Alternaria/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Cromatografia Líquida de Alta Pressão , Cucumis sativus/química , Contaminação de Alimentos/análise , Fungicidas Industriais/farmacologia , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/crescimento & desenvolvimento , Poluentes do Solo/química , Poluentes do Solo/farmacologia , Estereoisomerismo , Espectrometria de Massas em Tandem , Triazóis/farmacologia
3.
J Environ Sci (China) ; 85: 129-137, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471019

RESUMO

Benzotriazole UV stabilizers (BT-UVs) have attracted concerns due to their ubiquitous occurrence in the aquatic environment, and their bioaccumulative and toxic properties. However, little is known about their aquatic environmental degradation behavior. In this study, photodegradation of a representative of BT-UVs, 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P), was investigated under simulated sunlight irradiation. Results show that UV-P photodegrades slower under neutral conditions (neutral form) than under acidic or alkaline conditions (cationic and anionic forms). Indirect photodegradation is a dominant elimination pathway of UV-P in coastal seawaters. Dissolved organic matter (DOM) from seawaters accelerate the photodegradation rates mainly through excited triplet DOM (3DOM⁎), and the roles of singlet oxygen and hydroxyl radical are negligible in the matrixes. DOM from seawaters impacted by mariculture exhibits higher steady-state concentration of 3DOM⁎ ([3DOM⁎]) relative to those from pristine seawaters, leading to higher photosensitizing effects on the photodegradation. Halide ions inhibit the DOM-sensitized photodegradation of UV-P by decreasing [3DOM⁎]. Photodegradation half-lives of UV-P are estimated to range from 24.38 to 49.66 hr in field water bodies of the Yellow River estuary. These results are of importance for assessing environmental fate and risk UV-P in coastal water bodies.


Assuntos
Protetores Solares/química , Triazóis/química , Poluentes Químicos da Água/química , Fotólise , Água do Mar
4.
Chem Asian J ; 14(19): 3380-3385, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31478313

RESUMO

An oligonucleotide of triazole-linked RNA (TL RNA) was synthesized by performing consecutive copper-catalyzed azide-alkyne cycloaddition reactions for elongation. The reaction conditions that had been optimized for the synthesis of 3-mer TL RNA were found to be inappropriate for longer oligonucleotides, and the conditions were reoptimized for the solid-phase synthesis of an 11-mer TL RNA oligonucleotide. Duplex formation of the 11-mer TL RNA oligonucleotide was examined with the complementary oligonucleotide of natural RNA to reveal the effects of the 2'-OH groups on the duplex stability.


Assuntos
Oligonucleotídeos/química , RNA/química , Triazóis/química , Alquinos/química , Azidas/química , Catálise , Cobre/química , Reação de Cicloadição , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Oligonucleotídeos/síntese química , Técnicas de Síntese em Fase Sólida
5.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
6.
Chem Commun (Camb) ; 55(71): 10627-10630, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31429450

RESUMO

We report the synthesis of a novel hydroxyl-functionalised heteroleptic bis-NHC gold(i) complex that permits conjugation to various amines via carbamate bond formation. The resulting derivatives were studied in vitro using cell proliferation assays and fluorescent microscopic imaging of human cancer cell lines.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Carbamatos/química , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Ouro/química , Células A549 , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Doxorrubicina/química , Humanos , Imagem Óptica , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Triazóis/química
7.
J Agric Food Chem ; 67(36): 10256-10264, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433628

RESUMO

In this study, a simple and effective chiral analytical method was developed to monitor prothioconazole and prothioconazole-desthio at the enantiomeric level using supercritical fluid chromatography-tandem triple quadrupole mass spectrometry. The baseline enantioseparation for prothioconazole and prothioconazole-desthio was achieved within 2 min on a Chiralcel OD-3 column with CO2/0.2% acetic acid-5 mmol/L ammonium acetate 2-propanol (85:15, v/v) as the mobile phase at a flow rate of 1.5 mL/min and column temperature of 25 °C. The limit of quantitation for each enantiomer was 5 µg/kg, with a baseline resolution of >3.0. The results of enantioselective dissipation showed that R-(-)-prothioconazole was preferentially degraded in tomato, cucumber, and pepper under greenhouse conditions. S-(-)-prothioconazole-desthio was preferentially degraded in tomato and cucumber; however, R-(+)-prothioconazole-desthio was preferentially degraded in pepper. Results of this study may help to facilitate more accurate risk assessment of prothioconazole and its major metabolite in agricultural products.


Assuntos
Cucumis sativus/química , Fungicidas Industriais/química , Lycopersicon esculentum/química , Triazóis/química , Triazóis/metabolismo , Cromatografia com Fluido Supercrítico , Cucumis sativus/metabolismo , Lycopersicon esculentum/metabolismo , Piper nigrum/química , Piper nigrum/metabolismo , Estereoisomerismo , Espectrometria de Massas em Tandem , Verduras/química , Verduras/metabolismo
8.
Chemistry ; 25(55): 12712-12718, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433877

RESUMO

Arylated cyclobutanes were accessed by a versatile palladium-catalyzed secondary C(sp3 )-H activation, exploiting chelation assistance by modular triazoles. The C-H arylation led to cyclobutane natural product derivatives in a highly regioselective fashion, setting the stage for the easy access to novel fluorogenic boron-dipyrrin (BODIPY)-labeled probes for live-cell imaging.


Assuntos
Rastreamento de Células/métodos , Ciclobutanos/química , Imagem Óptica/métodos , Triazóis/química , Boro , Compostos de Boro , Catálise , Quelantes/química , Estrutura Molecular , Paládio/química
9.
Sci Total Environ ; 691: 1119-1126, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31466193

RESUMO

Environmental pollution caused by microplastics (MPs) and pesticides has become a global challenge, and increasing evidence shows that MPs can adsorb organic pollutants which may affect their distribution and bioavailability. As widely used pesticides, triazole fungicides with potential environmental and human safety risks often coexist with MPs in the environment. Understanding the adsorption behavior is the basis of risk assessment of co-exposure of MPs and triazole fungicides. In this study, the adsorption behavior of three commonly used triazole fungicides on polystyrene (PS) was studied using adsorption test. The influences of PS particle size and environmental factors on adsorption capacity were evaluated, and the adsorption mechanisms were discussed. Results suggested that the adsorption kinetics and isotherm conformed to the Pseudo-second-order and Freundlich model, respectively. The order of adsorption and desorption capacity was hexaconazole (HEX) > myclobutanil (MYC) > triadimenol (TRI), which was positively correlated with LogKow of pesticides. To a certain extent, the decrease in PS particle size and change in solution pH value and increase in salt ion strength all contribute to increasing adsorption capacity. The main mechanisms of adsorption were hydrophobic and electrostatic interactions. MPs can adsorb and may become the source and sink of triazole fungicides in aqueous environments. Our results demonstrate that more attention should be given to the combined water pollution risk of MPs and triazoles fungicides.


Assuntos
Fungicidas Industriais/química , Plásticos/química , Poliestirenos/química , Triazóis/química , Adsorção , Interações Hidrofóbicas e Hidrofílicas , Cinética , Concentração Osmolar
11.
Eur J Med Chem ; 181: 111576, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400709

RESUMO

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.


Assuntos
Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Click , Citocinas/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Triazóis/farmacocinética
12.
Ecotoxicol Environ Saf ; 183: 109491, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377517

RESUMO

Triticonazole and prothioconazole are widely used systemic agricultural triazole fungicides both with a chiral center. In this work, the enantioselective degradation of triticonazole and prothioconazole in three types of soils were investigated under native conditions using reversed phase liquid chromatography-tandem mass spectrometry with a Chiralcel OD-RH column. The results indicated that the enantioselective degradation was observed with S-triticonazole and R-prothioconazole preferentially degraded and the degradation rate was fast with a half-life within 6 days. It was also found that the presence of earthworms can accelerate the degradation and further enhance degradation enantioselectivity of triticonazole and prothioconazole in soils. Moreover, the enantioselective of triticonazole and prothioconazole in earthworms were studied. The results showed that the bioaccumulation was enantioselective with R-triticonazole and S-prothioconazole preferentially accumulated, which was similar to the soil. Our findings suggest that the enantioselective toxicity and potential effects of the metabolites should be considered for more accurate assessment of ecological risks of triticonazole and prothioconazole to target and non-target species.


Assuntos
Ciclopentanos/metabolismo , Fungicidas Industriais/metabolismo , Oligoquetos/metabolismo , Poluentes do Solo/metabolismo , Solo/química , Triazóis/metabolismo , Animais , Biodegradação Ambiental , Ciclopentanos/química , Fungicidas Industriais/química , Poluentes do Solo/química , Estereoisomerismo , Triazóis/química
13.
Ecotoxicol Environ Saf ; 183: 109506, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386940

RESUMO

The aim of this study is to understand the levels and behaviour of the herbicide propoxycarbazone in environmental compartments, which are poorly characterized considering degradation products that might reach either surface water as groundwater or soil samples. To this end, an analytical method, based on ultra-high performance liquid chromatography (UHPLC) coupled with Orbitrap mass spectrometry (MS), has been developed to determine the parent compound and its transformation products in soils and water. In addition, a set of laboratory trials has been designed to address the dissipation process of propoxycarbazone formulation in both environmental substrates. The study revealed that the dissipation in water followed a first order kinetics and a non-linear "First Order Multi Compartment" model (FOMC) to soil. Relevant advances have been also achieved in terms of the analytical methodology, as far as the UHPLC-Orbitrap-MS technique allows the development of a retrospective screening of pesticide transformation products in water and soils. For this purpose, an accurate-mass database has been built and used for the post-run screening analysis with 9 transformation products. Photodegradation presumably plays an important role in the dissipation of propoxycarbazone. The results of UHPLC-Orbitrap-MS revealed that four transformation products were formed during the degradation process of the herbicide.


Assuntos
Benzoatos/química , Poluentes Ambientais/química , Herbicidas/química , Solo/química , Triazóis/química , Água/química , Benzoatos/análise , Poluentes Ambientais/análise , Recuperação e Remediação Ambiental , Herbicidas/análise , Fotólise , Triazóis/análise
14.
Chem Biodivers ; 16(10): e1900377, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436917

RESUMO

The series of novel Mannich bases were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative bacterial strains. The results showed that all compounds were less active than the drugs used as reference, but some of them had moderate potency against Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633. The presence of a phenyl ring in the position 4 of piperazine seems to be necessary for antibacterial activity in this class of compounds.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bases de Mannich/química , Staphylococcus epidermidis/efeitos dos fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triazóis/síntese química , Triazóis/química
15.
Food Chem ; 301: 125265, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31387046

RESUMO

A novel method for determination of triazole fungicides and their enantiomers in foods was developed by aqueous two-phase extraction (ATPE) coupled with two-dimensional liquid chromatography (2D-LC). With an aqueous two-phase system (ATPS) of ethanol/K2HPO4 as biphasic extractant, the effects of the ATPS composition, extraction temperature and time on extraction yields of triazole fungicides were investigated. Optimum conditions were concluded as follows: ethanol concentration 31% (w/w) and K2HPO4 concentration 21% (w/w), extraction temperature 60 °C, extraction time 21 min. Based on reversed-phase separation systems, a 2D-LC was constructed by optimizing chromatographic conditions and online heart-cutting procedures. As a result, eight triazole fungicides and their enantiomers were separated respectively on C18 and cellulose-tris (3,5-dimethylphenylcarbamate) stationary phases, revealing good linear relationship in the range of 0.1218-30.06 µg/mL (R2 ≥ 0.9984). The detection limits and recoveries were 0.03113-0.3525 µg/mL and 71.57-107.8%, respectively. The ATPE-2D-LC method was successfully applied to chiral analysis of triazole fungicides in fruits and vegetables.


Assuntos
Cromatografia Líquida/métodos , Frutas/química , Fungicidas Industriais/análise , Extração Líquido-Líquido/métodos , Triazóis/análise , Verduras/química , Fungicidas Industriais/química , Fungicidas Industriais/isolamento & purificação , Limite de Detecção , Estereoisomerismo , Triazóis/química , Triazóis/isolamento & purificação
16.
J Agric Food Chem ; 67(33): 9220-9231, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31347838

RESUMO

Slow-release fungicide formulations (azoxystrobin, epoxiconazole, and tebuconazole) shaped as pellets and granules in a matrix of biodegradable poly(3-hydroxybutyrate) and natural fillers (clay, wood flour, and peat) were constructed. Infrared spectroscopy showed no formation of chemical bonds between components in the experimental formulations. The formulations of pesticides had antifungal activity against Fusarium verticillioides in vitro. A study of biodegradation of the experimental fungicide formulations in the soil showed that the degradation process was mainly influenced by the type of formulation without significant influence of the type of filler. More active destruction of the granules led to a more rapid accumulation of fungicides in the soil. The content of fungicides present in the soil as a result of degradation of the formulations and fungicide release was determined by their solubility. Thus, all formulations are able to function in the soil for a long time, ensuring gradual and sustained delivery of fungicides.


Assuntos
Argila/química , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Fungicidas Industriais/química , Hidroxibutiratos/química , Poliésteres/química , Solo/química , Madeira/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos/instrumentação , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fungicidas Industriais/farmacologia , Fusarium/efeitos dos fármacos , Cinética , Pirimidinas/química , Pirimidinas/farmacologia , Estrobilurinas/química , Estrobilurinas/farmacologia , Triazóis/química , Triazóis/farmacologia
17.
Eur J Med Chem ; 179: 449-469, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271958

RESUMO

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4ß2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/tratamento farmacológico , Radioisótopos de Flúor/química , Marcação por Isótopo , Agonistas Nicotínicos/farmacologia , Tomografia por Emissão de Pósitrons , Quinuclidinas/farmacologia , Triazóis/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
18.
J Agric Food Chem ; 67(30): 8303-8311, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31298535

RESUMO

Exposure to chiral pesticides poses many potential health risks. In this study, we examined the impacts of exposure to penconazole and its enantiomers on gut microbiota and metabolic profiles in mice. The relative abundance of microbiota in cecal content significantly changed following exposure to penconazole and its enantiomers. At the genus level, the relative abundances of seven gut microflora were altered following exposure to (-)-penconazole. Both (±)-penconazole and (+)-penconazole caused significant changes in the relative abundances of five gut microflora. In addition, targeted serum metabolomics analysis showed disturbed metabolic profiles following exposure. Respectively, (±)-penconazole, (+)-penconazole, and (-)-penconazole exposure significantly altered the relative levels of 29, 23, and 36 metabolites. In general, exposure to penconazole and its enantiomers caused disorders in gut microbiota and metabolic profiles of mice. The potential health risks of penconazole and its enantiomers now require further evaluation.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos/metabolismo , Praguicidas/química , Praguicidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Trato Gastrointestinal/microbiologia , Masculino , Camundongos Endogâmicos ICR , Filogenia , Estereoisomerismo
19.
Int J Pharm Compd ; 23(4): 325-339, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315085

RESUMO

This analysis was designed to determine the efficacy of anastrozole, an aromatase inhibitor, combined with testosterone in a subcutaneous implant in preventing elevated estradiol levels and the subsequent side effects of excess estrogen associated with testosterone therapy. It also allowed for the establishment of normative ranges of serum testosterone levels on subcutaneous implant therapy. The study participants were 344 men who were accrued to an institutional review board-approved cohort study between April 2014 and 2017. Efficacy of the subcutaneous combination implant in maintaining low estradiol levels was evaluated. Serum levels of testosterone and estradiol were measured throughout the implant cycle, at week 4, and when symptoms returned. Correlations between patient demographics, dosing, and serum levels on therapy were evaluated. Mean testosterone dose was 1827 ± 262 mg. Mean anastrozole dose was 15.3 ± 3.2 mg with the majority of men receiving 16 mg of subcutaneous anastrozole. The mean interval of insertion was 4.8 months. Low estradiol levels were maintained throughout the implant cycle. Mean T level at week 4 was 1183 ± 315 ng/dl and 553 ± 239 ng/dl when symptoms returned. Levels of testosterone on therapy inversely correlated with body mass index. There were no adverse events attributed to testosterone or anastrozole therapy. Subcutaneous anastrozole delivered simultaneously with testosterone allowed for higher dosing of testosterone and less frequent intervals of insertion. Low-dose anastrozole released from the combination implant maintained low estradiol levels throughout the implant cycle and prevented clinical side effects attributed to excess estrogen.


Assuntos
Anastrozol , Inibidores da Aromatase/farmacologia , Estradiol/química , Testosterona , Anastrozol/uso terapêutico , Estudos de Coortes , Humanos , Masculino , Testosterona/uso terapêutico , Triazóis/química
20.
J Enzyme Inhib Med Chem ; 34(1): 1210-1217, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286781

RESUMO

In this study, a series of 4,5-bis(substituted phenyl)-4H-1,2,4-triazol-3-amine compounds was designed, synthesised, and evaluated to determine their potential as anti-lung cancer agents. According to the results of screening of lung cancer cell lines A549, NCI-H460, and NCI-H23 in vitro, most of the synthesised compounds have potent cytotoxic activities with IC50 values ranging from 1.02 to 48.01 µM. Particularly, compound 4,5-bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (BCTA) was the most potent anti-cancer agent, with IC50 values of 1.09, 2.01, and 3.28 µM against A549, NCI-H460, and NCI-H23 cells, respectively, meaning many-fold stronger anti-lung cancer activity than that of the chemotherapeutic agent 5-fluorouracil. We also explored the effects of BCTA on apoptosis in lung cancer cells by flow cytometry and western blotting. Our results indicated that BCTA induced apoptosis by upregulating proteins BAX, caspase 3, and PARP. Thus, the potential application of compound BCTA as a drug should be further examined.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Triazóis/síntese química , Triazóis/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Triazóis/química
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