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1.
Nat Commun ; 12(1): 831, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547306

RESUMO

The regulation of glutamate receptor localization is critical for development and synaptic plasticity in the central nervous system. Conventional biochemical and molecular biological approaches have been widely used to analyze glutamate receptor trafficking, especially for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors (AMPARs). However, conflicting findings have been reported because of a lack of useful tools for analyzing endogenous AMPARs. Here, we develop a method for the rapid and selective labeling of AMPARs with chemical probes, by combining affinity-based protein labeling and bioorthogonal click chemistry under physiological temperature in culture medium. This method allows us to quantify AMPAR distribution and trafficking, which reveals some unique features of AMPARs, such as a long lifetime and a rapid recycling in neurons. This method is also successfully expanded to selectively label N-methyl-D-aspartate-type glutamate receptors. Thus, bioorthogonal two-step labeling may be a versatile tool for investigating the physiological and pathophysiological roles of glutamate receptors in neurons.


Assuntos
Neurônios/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Coloração e Rotulagem/métodos , Animais , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Antagonistas de Aminoácidos Excitatórios/química , Fluoresceína/química , Corantes Fluorescentes/química , Expressão Gênica , Células HEK293 , Meia-Vida , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Neurônios/ultraestrutura , Cultura Primária de Células , Transporte Proteico , Quinoxalinas/química , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/química , Receptores de AMPA/genética , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética
2.
PLoS One ; 15(8): e0236839, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780746

RESUMO

The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 µM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteína Adaptadora GRB2/antagonistas & inibidores , Quinoxalinas/farmacologia , Animais , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Proteína Adaptadora GRB2/química , Proteína Adaptadora GRB2/metabolismo , Humanos , Células K562 , Rim/citologia , Cinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Ligação Proteica , Quinoxalinas/química , Quinoxalinas/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Ressonância de Plasmônio de Superfície , Peixe-Zebra , Domínios de Homologia de src
3.
Infect Genet Evol ; 84: 104451, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32640381

RESUMO

WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The ever-growing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Proteínas do Nucleocapsídeo/química , Proteínas do Envelope Viral/química , Proteínas da Matriz Viral/química , Vírion/efeitos dos fármacos , Amidas , Sequência de Aminoácidos , Antivirais/química , Betacoronavirus/genética , Betacoronavirus/metabolismo , Sítios de Ligação , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Carbamatos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Ciclopropanos , Doxiciclina/química , Doxiciclina/farmacologia , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas do Nucleocapsídeo/antagonistas & inibidores , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinoxalinas/química , Quinoxalinas/farmacologia , Rutina/química , Rutina/farmacologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Simeprevir/química , Simeprevir/farmacologia , Sulfonamidas , Termodinâmica , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Vírion/genética
4.
Food Chem ; 331: 127264, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32619906

RESUMO

This work aimed to develop a method permitting an informed choice of antioxidants to reduce carcinogenic heterocyclic aromatic amine (HAA) formation during proteinaceous food cooking. Therefore, a three-step approach was developed. First, the most promising antioxidants were selected using molecular modeling approaches. For this, analog design was used to highlight the most suitable antioxidants based on their diversification potential using bioisosteric replacement. Then, structure activity relationship studies allowed drawing the relevant properties for inhibiting HAA formation and explained partly the inhibitory activity. Secondly, the approved antioxidants were tested in ground beef patties to assess their inhibitory properties against HAA formation. Resveratrol was found to be the most efficient as it totally inhibited MeIQ and reduced MeIQx and PhIP formation by 40 and 70%, respectively. Finally, natural ingredients rich in these antioxidants were evaluated. Oregano was found to totally inhibit MeIQ formation and to reduce by half MeIQx and PhIP formation.


Assuntos
Antioxidantes/química , Culinária/métodos , Compostos Heterocíclicos/química , Carne Vermelha , Relação Estrutura-Atividade , Aminas/química , Animais , Bovinos , Modelos Moleculares , Origanum/química , Extratos Vegetais , Quinolinas/química , Quinoxalinas/química , Resveratrol/química , Chá , Vinho
5.
J Food Sci ; 85(7): 2090-2097, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32579728

RESUMO

The inhibitory effects of vitamins (nicotinic acid, pyridoxamine [PM], and l-ascorbic acid) and phenolic acids (ferulic acid and p-coumaric acid) on the formation of 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx) were studied in a glycine/glucose/creatinine model system and fried tilapia cakes. The results showed that PM was the most potential inhibitor and the inhibition rates reached 82.72% and 78.54% in model system and fried tilapia cakes, respectively. Detailed formation mechanism of MeIQx was put forward to find the inevitable species in the non-free radical formation mechanism of MeIQx. Dose-dependent analysis of PM on methylglyoxal (MGO ) and MeIQx formation were studied by using model systems and the results showed that MGO and MeIQx were both reduced about 60% in reaction mixtures when the molar ratio of PM to glycine was 1:16, which indicated that MGO is a key intermediate on the pathway of MeIQx formation. Quantum chemistry calculations showed that PM can act as a useful inhibitor to inhibit the formation of MeIQx and react with MGO to form new compounds. A pathway for the inhibitory activity of PM against MeIQx formation was proposed. PRACTICAL APPLICATION: Pyridoxamine was the most effective inhibitor against heterocyclic aromatic amines (HAAs) and could be applied to a variety of food systems. While the inhibitory mechanism is still unclear. Detailed formation mechanism of MeIQx was put forward first and suggested methylglyoxal as an inevitable species in the non-free radical formation mechanism of MeIQx in this study. Pyridoxamine trapping methylglyoxal is likely a key mechanism against the generation of MeIQx was demonstrated by quantum chemistry calculation and experimental demonstration. These findings may provide effective suggestions for reducing HAAs and similar toxicants in daily cuisine.


Assuntos
Aldeído Pirúvico/química , Quinoxalinas/química , Vitaminas/química , Aminas/química , Animais , Culinária , Produtos Pesqueiros/análise , Temperatura Alta , Hidroxibenzoatos/química , Mutagênicos/metabolismo , Piridoxamina/química , Tilápia
6.
Molecules ; 25(12)2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32560203

RESUMO

BACKGROUND: In recent decades, several viruses have jumped from animals to humans, triggering sizable outbreaks. The current unprecedent outbreak SARS-COV-2 is prompting a search for new cost-effective therapies to combat this deadly pathogen. Suitably functionalized polysubstituted quinoxalines show very interesting biological properties (antiviral, anticancer, and antileishmanial), ensuring them a bright future in medicinal chemistry. OBJECTIVES: Focusing on the promising development of new quinoxaline derivatives as antiviral drugs, this review forms part of our program on the anti-infectious activity of quinoxaline derivatives. METHODS: Study compiles and discusses recently published studies concerning the therapeutic potential of the antiviral activity of quinoxaline derivatives, covering the literature between 2010 and 2020. RESULTS: A final total of 20 studies included in this review. CONCLUSIONS: This review points to a growing interest in the development of compounds bearing a quinoxaline moiety for antiviral treatment. This promising moiety with different molecular targets warrants further investigation, which may well yield even more encouraging results regarding this scaffold.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Quinoxalinas/uso terapêutico , Vírus de DNA/efeitos dos fármacos , Humanos , Pandemias , Quinoxalinas/química , Relação Estrutura-Atividade
7.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441299

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
8.
Food Chem ; 327: 127056, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32447137

RESUMO

The method for seafood spoilage detection is far from satisfactory for ensuring food safety and security. Here, we develop a simple and cost-effective method using the filter papers loaded with a dihydroquinoxaline derivative (H + DQ2) to monitor salmon spoilage. The correlation between the content of solid biogenic amines and the photoluminescence intensity (PL) of H + DQ2 induced by amine vapours showed that the PL intensities of H + DQ2 increased with the increase of spoilage, which indicates that it is feasible to evaluate the spoilage degree of salmon based on the PL intensity of H + DQ2-loaded filter papers by semi-quantitation. The optimum detection condition is 75, 50 and 50 g of salmon, 75, 25 and 10 µM H + DQ2 at 0, 4 and 25 °C, respectively. This study provides a quick and simple way for testing amine vapour from fish and provides baseline information for developing an easy-to-use on-site method to evaluate seafood quality for customers.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Papel , Alimentos Marinhos/análise , Animais , Aminas Biogênicas/análise , Aminas Biogênicas/química , Contaminação de Alimentos/análise , Quinoxalinas/química , Salmão , Espectrometria de Fluorescência
9.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973234

RESUMO

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2-6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7-16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7-13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19-25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.


Assuntos
Compostos Heterocíclicos/síntese química , Indóis/síntese química , Nitrogênio/química , Piridazinas/síntese química , Quinoxalinas/síntese química , Enxofre/química , Triazóis/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Compostos Heterocíclicos/química , Ligação de Hidrogênio , Indóis/química , Conformação Molecular , Espectroscopia de Prótons por Ressonância Magnética , Piridazinas/química , Quinoxalinas/química , Triazóis/química , Difração de Raios X
10.
Talanta ; 210: 120612, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987202

RESUMO

A new strategy endowing probe with large Stokes shift, high quantum yield and red emission was developed by incorporating tetrahydroquinoxaline unit and five-membered pyrrolidine ring on fluorophore. As demonstrated, a novel probe was rationally designed and synthesized for sensitive monitor of cellular cysteine (Cys) and endogenous aminoacylase with large Stokes shift and high quantum yield.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Imagem Óptica , Pirrolidinas/química , Teoria Quântica , Quinoxalinas/química , Animais , Células Cultivadas , Corantes Fluorescentes/síntese química , Camundongos , Estrutura Molecular , Pirrolidinas/síntese química , Quinoxalinas/síntese química , Células RAW 264.7
11.
Eur J Med Chem ; 188: 111987, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31893549

RESUMO

Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Quinoxalinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
12.
J Enzyme Inhib Med Chem ; 35(1): 85-95, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707866

RESUMO

To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
13.
J Pharm Biomed Anal ; 178: 112964, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711865

RESUMO

Zepatier® (Elbasvir and Grazoprevir) is a novel two-drug, fixed-dose combination product containing elbasvir and grazoprevir used for the treatment of chronic hepatitis C virus infection. Various forced degradation studies of the two drugs had been conducted in order to identify significant degradation products and establish the degradation pathway induced by thermal, photolytic, acid/base hydrolytic and/or oxidative stress conditions. A reversed phase C18 UHPLC-PDA method has been developed for the analysis of the stressed samples. Seven significant degradation products of elbasvir and five significant degradation products of grazoprevir were found and investigated further by high resolution ESI-QTOF-MS with high accurate mass measurement (-1.96 to 1.36 ppm). The chemical structures of each degradation product were proposed based on their relative MS/MS fragmentation spectra in comparison with the corresponding parent drugs and the chemical synthetic knowledge of process chemists. The validated stability-indicating UHPLC method can be used in routine analysis for the simultaneous determination of elbasvir and grazoprevir in pharmaceutical formulations. As more and more combination drugs will enter into the market, this study can also shed light on stability indicating method development for combined drugs at early development stage.


Assuntos
Benzofuranos/química , Imidazóis/química , Quinoxalinas/química , Amidas , Antivirais/química , Carbamatos , Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos , Combinação de Medicamentos , Sulfonamidas , Espectrometria de Massas em Tandem/métodos
14.
Eur J Med Chem ; 186: 111894, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787361

RESUMO

Green chemistry is becoming the favored approach to preparing drug molecules in pharmaceutical industry. Herein, we developed a clean and efficient method to synthesize 3-benzoylquinoxalines via activated carbon promoted aerobic benzylic oxidation under "on-water" condition. Moreover, biological studies with this class of compounds reveal an antiproliferative profile. Further structure modifications are performed and the investigations exhibited that the most active 12a could inhibit the microtubule polymerization by binding to tubulin and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. In addition, molecular docking studies allow the rationalization of the pharmacodynamic properties observed. Our systematic studies provide not only guidance for applications of O2/AC/H2O system, but also a new scaffold targeting tubulin for antitumor agent discovery.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzil/química , Quinoxalinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carbono/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Formiatos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Oxirredução , Polimerização/efeitos dos fármacos , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Ácidos Sulfúricos/química , Ácido Trifluoracético/química
15.
Org Biomol Chem ; 18(1): 154-162, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31803883

RESUMO

2,7-Disubstituted oxazolo[5,4-f]quinoxalines were synthesized from 6-amino-2-chloroquinoxaline in four steps (iodination at C5, substitution of the chloro group, amidation and copper-catalysed cyclization) affording 28 to 44% overall yields. 2,8-Disubstituted oxazolo[5,4-f]quinoxaline was similarly obtained from 6-amino-3-chloroquinoxaline (39% overall yield). For the synthesis of other oxazolo[5,4-f]quinoxalines, amidation was rather performed before substitution; moreover, time-consuming purification steps were avoided between the amines and the final products (38 to 54% overall yields). Finally, a more efficient method involving merging of the last two steps in a sequential process was developed to access more derivatives (37 to 65% overall yields). Most of the oxazolo[5,4-f]quinoxalines were evaluated for their activity on a panel of protein kinases, and a few 2,8-disubstituted derivatives proved to inhibit GSK3 kinase. While experiments showed an ATP-competitive inhibition on GSK3ß, structure-activity relationships allowed us to identify 2-(3-pyridyl)-8-(thiomorpholino)oxazolo[5,4-f]quinoxaline as the most potent inhibitor with an IC50 value of about 5 nM on GSK3α.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade
16.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690898

RESUMO

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sítios Internos de Entrada Ribossomal/efeitos dos fármacos , Quinoxalinas/farmacologia , RNA Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Humanos , Sítios Internos de Entrada Ribossomal/genética , Conformação Molecular , Quinoxalinas/química , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
17.
ACS Chem Biol ; 14(12): 2810-2821, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31714738

RESUMO

Because of its multifaceted role in cellular functions, tubulin is a validated and productive drug target for cancer therapy. While many tubulin inhibitors demonstrate clinical efficacy, they are often limited by the development of multidrug resistance. Therefore, implementation of tubulin inhibitors that can overcome resistance could provide significant therapeutic benefits. To optimize our previously reported tubulin inhibitor, 4a, we designed and synthesized two new analogues, SB202 and SB204, based on the crystal structure of 4a in complex with tubulin protein. SB202 and SB204 achieved enhanced binding at the colchicine site in tubulin and also showed improved metabolic stability and antiproliferative potency in vitro. Functional studies confirmed that SB202 and SB204 inhibit tubulin polymerization, arrest cells in the G2/M phase of the cell cycle, interfere with cancer cell migration and proliferation, and enhance apoptotic cascades. When evaluated in vivo, SB202 exhibited antitumor and vascular disrupting action against paclitaxel-resistant mouse xenograft models, strongly suggesting the potential of this scaffold to overcome multidrug resistance for cancer therapy.


Assuntos
Antineoplásicos/química , Cristalografia por Raios X/métodos , Descoberta de Drogas/métodos , Quinoxalinas/química , Moduladores de Tubulina/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Colchicina/química , Humanos , Camundongos , Polimerização , Quinoxalinas/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
18.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752396

RESUMO

A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity for the prepared compounds was investigated against four bacterial species and two fungal strains. The symmetrically disubstituted quinoxalines 2, 3, 4, and 5 displayed the most significant antibacterial activity, while compounds 6a, 6b, and the pentacyclic compound 10 showed considerable antifungal activity. Furthermore, compounds 3f, 6b showed broad antimicrobial spectrum against most of the tested strains.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinoxalinas/química
19.
Molecules ; 24(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614764

RESUMO

Colorimetric indicators are versatile for applications such as intelligent packaging. By interacting with food, package headspace, and/or the ambient environment, color change in these indicators can be useful for reflecting the actual quality and/or monitoring distribution history (e.g., time and temperature) of food products. In this study, indicator dyes based on cinnamil and quinoxaline derivatives were synthesized using aroma compounds commonly present in food: diacetyl, benzaldehyde, p-tolualdehyde and p-anisaldehyde. The identities of cinnamil and quinoxaline derivatives were confirmed by Fourier transform infrared (FT-IR) spectroscopy, mass spectrometry (MS), 1H nuclear magnetic resonance (NMR) and 13C NMR analyses. Photophysical evaluation showed that the orange-colored cinnamil derivatives in dimethylsulfoxide (DMSO) turned to dark brownish coloration when exposed to strong alkalis. The cinnamil and acid-doped quinoxaline derivatives were sensitive to volatile amines commonly present during the spoilage in seafood. Quinoxaline derivatives doped by strong organic acid were effective as pH indicators for volatile amine detection, with lower detection limits than cinnamil. However, cinnamil exhibited more diverse color profiles than the quinoxaline indicators when exposed to ammonia, trimethylamine, triethylamine, dimethylamine, piperidine and hydrazine. Preliminary tests of acid-doped quinoxaline derivatives on fresh fish demonstrated their potential as freshness indicators in intelligent packaging applications.


Assuntos
Aminas/isolamento & purificação , Corantes/química , Embalagem de Alimentos , Compostos Orgânicos Voláteis/isolamento & purificação , Aminas/química , Animais , Benzaldeídos/química , Colorimetria , Diacetil/química , Dimetil Sulfóxido/química , Dimetilaminas/química , Peixes , Alimentos/normas , Humanos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Quinoxalinas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos Orgânicos Voláteis/química
20.
Future Med Chem ; 11(23): 2989-3004, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31659919

RESUMO

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them 13d was the most active (IC50 = 0.107 µM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/síntese química , Descoberta de Drogas/métodos , Inibidores Enzimáticos/síntese química , Quinoxalinas/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
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