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1.
Nat Commun ; 11(1): 4443, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895371

RESUMO

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.


Assuntos
Azóis/química , Técnicas de Química Sintética/métodos , Estereoisomerismo , Catálise , Estrutura Molecular , Triazóis/química
2.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
3.
J Chromatogr A ; 1623: 461154, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32505273

RESUMO

Chiral stationary phases (CSPs) have always been research hotspot in enantiomer separation. Currently, most of the CSPs are based on silica platform. In this research, monodisperse, porous glycidyl methacrylate-divinylbenzene copolymer particles (poly(GMA-DVB)) were designed and prepared. Then the GMA was further reacted with ethylenediamine to introduce amino groups onto the polymer, which provide anchoring sites for cellulose derivatives. Herein, Cellulose-tris (3,5-dimethylphenylcarbamate) (CDMPC) was successfully coated onto the polymer microspheres, achieving a stable and successful CSP. The porous structure and the surface moieties of the CSPs were studied in detail. The chromatographic separation was optimized. Hexaconazole,methyl DL-mandelate,benzoin and tebuconazole have been successfully separated on the CSP column, with column efficiency as high as 10,200 plates/m, which is comparable with some silica-based CSPs. The research has indicated that the poly(GMA-DVB) is a promising candidate for constructing CSPs for chiral separation.


Assuntos
Celulose/análogos & derivados , Microesferas , Fenilcarbamatos/química , Polímeros/química , Celulose/química , Cromatografia Líquida de Alta Pressão/métodos , Compostos de Epóxi/química , Metacrilatos/química , Porosidade , Dióxido de Silício/química , Estereoisomerismo , Triazóis/química , Compostos de Vinila/química
4.
Chemosphere ; 255: 126848, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388255

RESUMO

Insensitive high explosives are increasingly being used to replace more sensitive formulations, however large quantities of environmentally hazardous wastewater are generated from loading, assembling and packing processes. Currently, there is limited literature regarding the treatment of wastewater contaminated with these hazardous insensitive high explosive materials such as 1,3,5-trinitroperhydro- 1,3,5-triazine (RDX), 2,4-dinitoranisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO). The preferred method of explosive wastewater treatment is adsorption by activated carbon, usually through treatment columns or fluidised beds that are simple to operate and cost effective. The aim of this research was to assess whether commercially available activated carbons would be suitable and economically viable to treat explosive wastewater containing RDX, DNAN and NTO. Bottle point tests were used to determine adsorption capacity and adsorption kinetics for the individual insensitive high explosives with three different activated carbons. Equilibrium data were fitted to the Langmuir, Freundlich and Temkin isotherms to determine the mechanisms of adsorption. Six hour bottle point tests for a mixture of the three insensitive high explosive constituents were used to consider possible preferential adsorption. As expected, RDX and DNAN were adsorbed at concentrations up to 40 mg.L-1 and 150 mg.L-1 respectively by the activated carbons tested, demonstrating the viability of treatment by adsorption. However, at the high concentrations of NTO expected in wastewater (1400 mg.L-1) activated carbons were rapidly saturated, suggesting that treatment of NTO contaminated wastewater would require prohibitively large quantities of activated carbon compared to RDX and DNAN.


Assuntos
Anisóis/química , Carvão Vegetal/química , Nitrocompostos/química , Triazinas/química , Triazóis/química , Adsorção , Substâncias Explosivas , Cinética , Modelos Químicos , Águas Residuárias
5.
Mol Pharmacol ; 98(1): 49-60, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32358164

RESUMO

Negative allosteric modulation of the metabotropic glutamate 5 (mGlu5) receptor has emerged as a potential strategy for the treatment of neurologic disorders. Despite the success in preclinical studies, many mGlu5 negative allosteric modulators (NAMs) that have reached clinical trials failed due to lack of efficacy. In this study, we provide a detailed in vitro pharmacological characterization of nine clinically and preclinically tested NAMs. We evaluated inhibition of l-glutamate-induced signaling with Ca2+ mobilization, inositol monophosphate (IP1) accumulation, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and real-time receptor internalization assays on rat mGlu5 expressed in HEK293A cells. Moreover, we determined association rates (kon) and dissociation rates (koff), as well as NAM affinities with [3H]methoxy-PEPy binding experiments. kon and koff values varied greatly between the nine NAMs (34- and 139-fold, respectively) resulting in long receptor residence times (>400 min) for basimglurant and mavoglurant, medium residence times (10-30 min) for AZD2066, remeglurant, and (RS)-remeglurant, and low residence times (<10 mins) for dipraglurant, F169521, F1699611, and STX107. We found that all NAMs inhibited l-glutamate-induced mGlu5 receptor internalization, generally with a similar potency to IP1 accumulation and ERK1/2 phosphorylation, whereas Ca2+ mobilization was less potently inhibited. Operational model of allosterism analyses revealed that dipraglurant and (RS)-remeglurant were biased toward (affinity) receptor internalization and away (cooperativity) from the ERK1/2 phosphorylation pathway, respectively. Our study is the first to measure mGlu5 NAM binding kinetics and negative allosteric modulation of mGlu5 receptor internalization and adds significant new knowledge about the molecular pharmacology of a diverse range of clinically relevant NAMs. SIGNIFICANCE STATEMENT: The metabotropic glutamate 5 (mGlu5) receptor is important in many brain functions and implicated in several neurological pathologies. Negative allosteric modulators (NAMs) have shown promising results in preclinical models but have so far failed in human clinical trials. Here we provide the most comprehensive and comparative molecular pharmacological study to date of nine preclinically/clinically tested NAMs at the mGlu5 receptor, which is also the first study to measure ligand binding kinetics and negative allosteric modulation of mGlu5 receptor internalization.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Isoxazóis/farmacologia , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Triazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Cálcio/metabolismo , Células HEK293 , Humanos , Imidazóis/química , Indóis/química , Fosfatos de Inositol/metabolismo , Isoxazóis/química , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Piridinas/química , Ratos , Fatores de Tempo , Triazóis/química
6.
Pharm Res ; 37(6): 94, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32405662

RESUMO

PURPOSE: An investigation of underlying mechanisms of API-polymer interaction patterns has the potential to provide valuable insights for selecting appropriate formulations with superior physical stability and processability. MATERIALS AND METHODS: In this study, copovidone was used as a polymeric carrier for several model compounds including clotrimazole, nifedipine, and posaconazole. The varied chemical structures conferred the ability for the model compounds to form distinct interactions with copovidone. Rheology and nuclear magnetic resonance (NMR) were combined to investigate the molecular pattern and relative strength of active pharmaceutical ingredient (API)-polymer interactions. In addition, the impact of the interactions on formulation processability via hot melt extrusion (HME) and physical stability were evaluated. RESULTS: The rheological response of an API-polymer system was found to be highly sensitive to API-polymer interaction, depending both on API chemistry and API-polymer miscibility. In the systems studied, dispersed API induced a stronger plasticizer effect on the polymer matrix compared to crystalline/aggregated API. Correspondingly, the processing torque via HME showed a proportional relationship with the maximum complex viscosity of the API-polymer system. In order to quantitatively evaluate the relative strength of the API-polymer interaction, homogeneously dispersed API-polymer amorphous samples were prepared by HME at an elevated temperature. DSC, XRD, and rheology were employed to confirm the amorphous integrity and homogeneity of the resultant extrudates. Subsequently, the homogeneously dispersed API-polymer amorphous dispersions were interrogated by rheology and NMR to provide a qualitative and quantitative assessment of the nature of the API-polymer interaction, both macroscopically and microscopically. Rheological master curves of frequency sweeps of the extrudates exhibited a strong dependence on the API chemistry and revealed a rank ordering of the relative strength of API-copovidone interactions, in the order of posaconazole > nifedipine > clotrimazole. NMR data provided the means to precisely map the API-polymer interaction pattern and identify the specific sites of interaction from a molecular perspective. Finally, the impact of API-polymer interactions on the physical stability of the resultant extrudates was studied. CONCLUSION: Qualitative and quantitative evaluation of the relative strength of the API-polymer interaction was successfully accomplished by utilizing combined rheology and NMR. Graphical Abstract.


Assuntos
Clotrimazol/química , Portadores de Fármacos/química , Nifedipino/química , Pirrolidinas/química , Triazóis/química , Compostos de Vinila/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Elasticidade , Tecnologia de Extrusão por Fusão a Quente , Temperatura Alta , Espectroscopia de Ressonância Magnética , Conformação Molecular , Reologia , Relação Estrutura-Atividade , Viscosidade
7.
Food Chem ; 328: 127098, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32470775

RESUMO

Poly(1H-1,2,4-triazole-3-thiol) (poly(T3T)) conductive film was coated successfully on the gold electrode (Au). The electrochemical behavior of vanillin (VAN) was studied on the 1H-1,2,4-triazole-3-thiol-Au (T3T-Au) electrode. The determination of VAN was performed on the T3T-Au electrode using a differential pulse voltammetry (DPV) technique. In order to detect the concentration of VAN, suitable supporting electrolyte solution and pH value were determined. At pH 3 in HClO4 solution, the anodic peak current of VAN obtained with the T3T-Au electrode is 4.3 times greater than the bare Au electrode. The response oxidation peak current and concentration of VAN showed a good linear relationship in the range of 0.1-11.3 µM. The limit of detection was found as 0.04 µM. Besides, the reproducibility, repeatability, stability, and interference measurements were also assayed. This sensor was applied successfully for the detection of VAN in synthetic samples and various food samples.


Assuntos
Benzaldeídos/análise , Benzaldeídos/química , Eletroquímica/instrumentação , Ouro/química , Polímeros/química , Compostos de Sulfidrila/química , Triazóis/química , Eletrodos , Oxirredução , Reprodutibilidade dos Testes
8.
PLoS One ; 15(4): e0231315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315346

RESUMO

Although fungicides could be the best solution in combating fungal infections in crops, however, the phytotoxic level of fungicides to the crops should be tested first to ensure that it is safe for the crops. Moreover, nanocarrier systems of fungicides could play a significant role in the advancement of crop protection. For this reason, chitosan was chosen in the present study as a nanocarrier for fungicides of hexaconazole and/or dazomet in the development of a new generation of agronanofungicides with a high antifungal potent agent and no phytotoxic effect. Hence, the encapsulation of fungicides into the non-toxic biopolymer, chitosan was aims to reduce the phytotoxic level of fungicides. In the present study, the in vivo phytotoxicity of chitosan-fungicides nanoparticles on the physiological and vegetative growth of oil palm seedlings was evaluated in comparison to its pure fungicides as well as the conventional fungicides. The results revealed the formation of chitosan-fungicides nanoparticles could reduce the phytotoxic effect on oil palm seedlings compared to their counterparts, pure fungicides. The chitosan-fungicides nanoparticles were seen to greatly reduce the phytotoxic effect compared to the conventional fungicides with the same active ingredient.


Assuntos
Arecaceae/efeitos dos fármacos , Quitosana/química , Proteção de Cultivos , Fungicidas Industriais/toxicidade , Doenças das Plantas/prevenção & controle , Plântula/efeitos dos fármacos , Arecaceae/crescimento & desenvolvimento , Fungicidas Industriais/química , Nanopartículas/química , Nanopartículas/toxicidade , Plântula/crescimento & desenvolvimento , Tiadiazinas/química , Tiadiazinas/toxicidade , Triazóis/química , Triazóis/toxicidade
9.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química
10.
Bull Environ Contam Toxicol ; 104(5): 689-700, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32303813

RESUMO

In this study, the hydrolysis of amisulbrom in buffer solutions and natural water samples were investigated. Effects of pH and temperature were tested in buffer solutions. Amisulbrom was stable in acidic and neutral aqueous solutions at 25°C, while quickly hydrolyzed with a half-life of 4.5 days (25°C) at pH 9.0. The kinetics rate equation was determined as k = 1.0234 × 1010 exp (-61.3760/R·T) (R2 = 0.9642) for hydrolysis of amisulbrom at pH 9.0. The pH, ionic strength, and solubility were important factors influencing the hydrolysis of amisulbrom in natural water samples. Furthermore, three hydrolysis products were separated and identified in buffer solution (pH 9.0) and natural water samples. A tentative transformation mechanism of amisulbrom was proposed to rationalize the formation of HPs (hydrolysis products) based on their structural identification, DFT (density functional theory), and hydrolysis profiles. Toxicity prediction using the quantitative structure-activity relationship model revealed that the HP-I, and HP-II were more toxic than the parent amisulbrom. This investigation was the first to evaluate the behavior of amisulbrom hydrolysis in aquatic systems.


Assuntos
Água Doce/química , Indóis/química , Modelos Químicos , Praguicidas/química , Triazóis/química , Poluentes Químicos da Água/química , Tampões (Química) , Água Doce/análise , Concentração de Íons de Hidrogênio , Hidrólise , Indóis/análise , Cinética , Modelos Moleculares , Estrutura Molecular , Concentração Osmolar , Praguicidas/análise , Solubilidade , Soluções , Temperatura , Triazóis/análise , Poluentes Químicos da Água/análise
11.
Nature ; 579(7799): 379-384, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188949

RESUMO

Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1-4 or linear processes5-9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon-nitrogen cross-couplings11 in a photochemical module-all without instrument reconfiguration.


Assuntos
Técnicas de Química Sintética/instrumentação , Técnicas de Química Sintética/métodos , Triazóis/síntese química , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Automação/instrumentação , Automação/métodos , Carbono/química , Indicadores e Reagentes/química , Nitrogênio/química , Oxirredução , Processos Fotoquímicos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Software , Soluções/química , Triazóis/química
12.
Chem Biol Interact ; 323: 109074, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32217108

RESUMO

Non-small-cell lung cancer (NSCLC) is one of the common malignant tumors, and multidrug resistance (MDR) and tumor metastasis limit the anticancer effect of NSCLC. Therefore, it is necessary to develop new anticancer drug that can inhibit MDR and metastasis of NSCLC. In the present study, we found that 5-(2-chlorophenyl)-4-(4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl)-2H-1,2,3- triazole (MAY) displayed strong cytotoxic effect on A549 and taxol-resistant A549 cells (A549/Taxol cells). We further discovered that MAY led to G2/M phase arrest by inhibiting microtubule polymerization in both cells. Then MAY caused apoptosis by the mitochondrial pathway in A549 cells and through the extrinsic pathway in A549/Taxol cells. Interestingly, MAY was not a substrate for P-glycoprotein (P-gp), which was highly expressed in A549/Taxol cells, and MAY inhibited the expression and efflux function of P-gp. Furthermore, MAY inhibited epithelial-mesenchymal transition (EMT) by targeting Twist1 in A549/Taxol cells. In summary, our results suggest that MAY induces apoptosis in A549 and A549/Taxol cells and inhibits EMT in A549/Taxol cells. These findings suggest that MAY could provide a promising method for the treatment of NSCLC, especially for the treatment of resistant NSCLC.


Assuntos
Apoptose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Paclitaxel/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/química , Polimerização , Transdução de Sinais/efeitos dos fármacos , Triazóis/química , Moduladores de Tubulina/química , Proteína 1 Relacionada a Twist/metabolismo
13.
J Environ Sci Health B ; 55(5): 438-446, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180509

RESUMO

The widespread application of triazole fungicides makes people attach great concern over its adverse effects in mammalian. In this paper, cytotoxic effects of triazole alcohol fungicides (TAFs) were assessed on human HeLa, A549, HCT116 and K562 cells, and the potential mechanism of TAFs cytotoxicity was studied preliminarily. Results showed that TAFs had cytotoxicity on human cells with different level and cytotoxic selectivity. TAFs cytotoxicity was resonated with a typical hormetic biphasic dose action that produced a complex pattern of stimulatory or inhibitory effects on cell viability. Among the five TAFs, diniconazole revealed a widest range of cytotoxicity to inhibit the viability of the adherent and the suspension cells, causing HeLa cells shrinkage, A549 cells shrunken, and K562 cells collapse, and showed stronger cytotoxicity than hexaconazole. Moreover, the involvement of ROS generation in the cytotoxicity of TAFs on human cells was observed, and the apoptosis of HeLa cells and the formation of apoptotic body in K562 cells induced by diniconazole were characterized. The results indicated the cytotoxicity of TAFs with different structures on human cells was depended on their own property and cell specificity, K562 cells were the most susceptible to TAFs and diniconazole was the strongest toxic.


Assuntos
Fungicidas Industriais/toxicidade , Células A549 , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Células K562 , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade , Triazóis/química , Triazóis/toxicidade
14.
J Med Chem ; 63(8): 3935-3955, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32212732

RESUMO

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Descoberta de Drogas/métodos , Triazóis/química , Triazóis/farmacologia , 5'-Nucleotidase/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Cristalografia por Raios X/métodos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos
15.
Food Chem ; 315: 126276, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014669

RESUMO

Cellulose nanofibers (CNF) coated with inorganic nanoparticles are novel hybrid nanocomposites that have great potential in various areas including agriculture and food science. The objectives of this study were to synthesize nanocomposites consisted of CNF coated with silver nanoparticles (AgNPs), which can be used as a surface-enhanced Raman spectroscopy (SERS) platform for measuring pesticides in Oolong tea. CNF were coated with AgNPs to form uniform CNF-AgNP nanocomposites that were investigated by transmission electron microscopy. Three-dimensional and porous CNF structures were loaded with AgNPs with an average size of 41 nm. CNF-AgNP substrates were applied in characterization and measurement of flusilazole in Oolong tea samples by SERS. A detection limit of 0.5 mg/kg for flusilazole was obtained based on partial least squares (PLS) regression analysis. These results indicate that CNF-AgNP nanocomposites combined with SERS is an accurate, sensitive, and efficient technique for identification and quantification of pesticide residues in Oolong tea.


Assuntos
Celulose/química , Nanopartículas Metálicas/química , Nanocompostos/química , Nanofibras/química , Silanos/química , Prata/química , Chá/química , Triazóis/química , Limite de Detecção , Análise Espectral Raman , Propriedades de Superfície
16.
Food Chem ; 317: 126434, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32106007

RESUMO

A triazole-stabilized fluorescence sensor is developed for copper detection in the study. Tris-(benzyltriazolylmethyl)amine (TBTA) is used to improve the sensitivity and stability for the sensing system. A series of comparative experiments are performed with and without TBTA. In the presence of TBTA, the fluorescence decrease ratio is enhanced from 2.46 to 118.25; the detection limit is reduced from 67 nM to 3.6 nM; the higher selectivity toward copper compared to the other metal ions is verified, including K+, Ca2+, Cd2+, Zn2+, Mg2+, Mn2+, Pb2+, Hg2+, Fe3+ and Cr3+. Besides, the sensing system is successfully applied for copper determination in complex tea samples and chicken feed samples with the recovery range of 91.67-116.8%. A good consistency between the presented sensor and the flame atom absorbance spectrometry (FAAS) is confirmed by the low relative errors with the range from -2.39% to 7.02%.


Assuntos
Ração Animal/análise , Cobre/análise , Análise de Alimentos/métodos , Espectrometria de Fluorescência/métodos , Chá/química , Fluorescência , Corantes Fluorescentes/química , Limite de Detecção , Metais/análise , Compostos Organometálicos/química , Sensibilidade e Especificidade , Triazóis/química
17.
J Environ Sci Health B ; 55(6): 509-516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32037956

RESUMO

This study investigates the interaction between tebuconazole and bovine serum albumin (BSA) in a physiological buffer (pH = 7.4) using the fluorescence quenching method to obtain the apparent binding constants (K) and number of binding sites (n) in the interaction between tebuconazole and BSA. The results revealed that tebuconazole can quench the intrinsic fluorescence of BSA through a static quenching procedure. It also shows that the thermodynamic parameters of enthalpy change (ΔH) and entropy change (ΔS) are negative, indicating that the interaction of tebuconazole with BSA is mainly driven by van der Waals forces and hydrogen bonds. The process of binding was a spontaneous process in which Gibbs free energy change was negative. The distance of r between the donor (BSA) and acceptor (tebuconazole) was calculated to be 0.68 nm based on Forster's non-radiative energy transfer theory. Analysis of synchronous fluorescence, three-dimensional fluorescence and circular dichroism (CD) spectra demonstrates that tebuconazole can induce conformational changes of BSA.


Assuntos
Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Triazóis/metabolismo , Sítios de Ligação , Dicroísmo Circular , Entropia , Fluorescência , Ligação de Hidrogênio , Conformação Proteica , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Termodinâmica , Triazóis/química , Triazóis/toxicidade
18.
Environ Sci Pollut Res Int ; 27(8): 7823-7834, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31889267

RESUMO

Reptiles are an important part of vertebrates and are the primitive terrestrial vertebrates. However, lots of reptile species are endangered or susceptible to extinction. It is no doubt that contaminants are one of the important reasons for the decline of the lizard population. In this study, the selective metabolism of triadimenol (TN) in the male Eremias argus lizards and the toxic effects of TN on lizards were studied. TN chiral isomers were separated and detected by HPLC-MS/MS system with Lux Cellulose-1 column. Tissue distribution experiments showed the existence of stereoselectivity biotransformation of TN enantiomers among organs in lizards, and RR-TN preferentially emerged over the other enantiomers. The antioxidant enzymes (SOD, CAT, GST) activities and MDA content assays demonstrated that TN induced oxidative stress in most organs, especially in the liver, and the histopathology analysis showed the severe liver and testis damage caused by 14-day continuous TN gavage. The reproductive effects of TN-induced reflected in the increased sex hormone testosterone. This research confirms that TN could induce hepatic and reproductive toxicity of E. argus lizard.


Assuntos
Fungicidas Industriais , Lagartos , Triazóis/análise , Animais , Masculino , Espectrometria de Massas em Tandem , Triazóis/química
19.
Dalton Trans ; 49(4): 1207-1219, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903475

RESUMO

Two types of ruthenium(ii) complexes containing 1,2,4-triazolo[1,5-a]pyrimidines of the general formulas [RuCl2(dmso)3(L)] ((1)-(3)) and [RuCl2(dmso)2(L)2] ((4)-(6)), where L represents 1,2,4-triazolo[1,5-a]pyrimidine (tp for (1)), 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp for (2)), 7-isobutyl-5-methyl-1,2,4-trizolo[1,5-a]pyrimidine (ibmtp for (3)), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for (4)), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp for (5)) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp for (6)), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, and 15N), and X-ray (for (3), (4), and (5)). All these complexes have been thoroughly screened for their in vitro cytotoxicity against melanoma cell lines A375 and Hs294T, indicating cis,cis,cis-[RuCl2(dbtp)2(dmso)2] (5) as the most active representative, in addition to being non-toxic to normal human fibroblasts (NHDF) and not inducing hemolysis of human erythrocytes. In order to develop an intravenous formulation for (5), liposomes composed of soybean phosphatidylcholine (SPC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) were prepared and subsequently characterized. (5)-Loaded liposomes, with spherical morphology, assessed by transmission electron microscope (TEM), exhibited satisfactory encapsulation efficiency and stability. In in vitro experiments, PEG-modified (5)-loaded liposomes were more effective (10-fold) than free (5) for growth inhibition of both human melanoma cell lines. Furthermore, such an approach resulted in the reduction of cancer cell viability that was even 10-fold greater than that observed for free cisplatin.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Lipossomos/química , Melanoma/patologia , Nanoestruturas/química , Pirimidinas/química , Rutênio/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Cápsulas , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Humanos , Interações Hidrofóbicas e Hidrofílicas , Triazóis/química
20.
J Enzyme Inhib Med Chem ; 35(1): 398-403, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899979

RESUMO

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Indóis/farmacologia , Triazóis/farmacologia , Animais , Antifúngicos/química , Candida/enzimologia , Candida/metabolismo , Linhagem Celular , Ergosterol/antagonistas & inibidores , Ergosterol/biossíntese , Feminino , Humanos , Indóis/química , Camundongos , Testes de Sensibilidade Microbiana , Especificidade da Espécie , Triazóis/química
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