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1.
Molecules ; 27(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35956876

RESUMO

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35-8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.


Assuntos
Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinoxalinas/química , Relação Estrutura-Atividade
2.
Molecules ; 27(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35956990

RESUMO

A sunlight-promoted sulfenylation of quinoxalin-2(1H)-ones using recyclable graphitic carbon nitride (g-C3N4) as a heterogeneous photocatalyst was developed. Using the method, various 3-sulfenylated quinoxalin-2(1H)-ones were obtained in good to excellent yields under an ambient air atmosphere. Moreover, the heterogeneous catalyst can be recycled at least six times without significant loss of activity.


Assuntos
Quinoxalinas , Luz Solar , Catálise , Luz
3.
Theranostics ; 12(10): 4564-4580, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832090

RESUMO

Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune "cold" tumor into "hot" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.


Assuntos
Fibroblastos Associados a Câncer , Receptores de Fatores de Crescimento de Fibroblastos , Linfócitos T , Neoplasias de Mama Triplo Negativas , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinoxalinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral
4.
J Org Chem ; 87(14): 9282-9295, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35786893

RESUMO

PhI(OAc)2-mediated ring expansion via 1,2-bond migration and concurrent solvent insertion generate hydroxylated polycyclic pyrrolo/indolo[1,2-a]quinoxaline-fused lactam derivatives in a highly diastereoselective fashion from spiro-fused quinoxalines in good-to-excellent yield. X-ray crystal structure analysis reveals that the polycyclic lactams are nonplanar molecules devoid of any symmetry as they possess one or two axially chiral biaryl or N-arylindolyl bridges along with one chiral center at the bridgehead carbon.


Assuntos
Lactamas , Quinoxalinas , Ciclização , Solventes
5.
Org Biomol Chem ; 20(28): 5558-5565, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35791887

RESUMO

In this paper, two cationic probes 1a and 1b and a neutral dye 1c were successfully designed and synthesized according to the Knoevenagel condensation reaction, which combines the good optical properties of hemocyanine and the biocompatibility of nitrogen-containing heterocyclic rings based on a quinoxaline skeleton. Probes 1a and 1b showed an OFF-ON fluorescence response to nucleic acids with excellent selectivity. Specifically, the fluorescence intensity of probe 1a was enhanced by 18 and 133 times, respectively, along with the increase of DNA or RNA concentrations (0-600 µg mL-1). Furthermore, a good linear correlation between the fluorescence intensity of probes 1a and 1b and the concentrations of DNA or RNA (0-350 µg mL-1) was obtained. In particular, the maximum emission wavelengths of probes 1a and 1b reached the near-infrared region (660-664 nm) when DNA or RNA was detected, which might reduce the light damage to cells and facilitate cell experiments. Fluorescence imaging revealed that all three dyes could be localized in the mitochondria of HeLa cells. The difference was that probes 1a and 1b could stain the nucleic acid in the mitochondria, while dye 1c was only a neutral mitochondrial biomarker. The results indicated that probes 1a and 1b are promising in the development of low toxicity mitochondrial nucleic acid probes and are expected to be used in monitoring the normal state of mitochondrial nucleic acids for living cells, which will help improve the situation in that currently reported studies of fluorescent probes are mainly focused on the nucleic acids in the nucleus, but less so on DNA in the mitochondria.


Assuntos
Corantes Fluorescentes , Ácidos Nucleicos , Células HeLa , Humanos , Mitocôndrias , Quinoxalinas , RNA , Esqueleto
6.
Viruses ; 14(7)2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35891520

RESUMO

Using data from the German Hepatitis C-Registry (Deutsche Hepatitis C-Register, DHC-R), we report the real-world safety and effectiveness of glecaprevir/pibrentasvir (GLE/PIB) treatment and its impact on patient-reported outcomes (PROs) in underserved populations who are not typically included in clinical trials, yet who will be crucial for achieving hepatitis C virus (HCV) elimination. The DHC-R is an ongoing, non-interventional, multicenter, prospective, observational cohort study on patients treated for chronic HCV infection in Germany. The data cutoff was 17 January 2021. The primary effectiveness endpoint was sustained virologic response at post-treatment Week 12 (SVR12). Safety outcomes were assessed in all patients receiving GLE/PIB. PROs were assessed using the SF-36 survey. Of 2354 patients, 1964 had valid SVR12 data (intention-to-treat analysis). Of these, 1905 (97.0%) achieved SVR12 with rates similar across the comorbidities analyzed, except for people who actively use drugs (PWUD (active)) (86.4%). Excluding those who discontinued treatment and did not achieve SVR12, or were reinfected with HCV, the rate was 99.3%, with similar results regardless of comorbidity. PWUD (active) and those with psychiatric disorders had the most meaningful improvements in PROs. Adverse events (AEs) occurred in 631/2354 patients (26.8%), and serious AEs in 44 patients (1.9%). GLE/PIB was highly effective and well tolerated in this real-world study of patient groups key to HCV elimination.


Assuntos
Hepatite C Crônica , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis , Ciclopropanos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Medidas de Resultados Relatados pelo Paciente , Prolina/análogos & derivados , Estudos Prospectivos , Pirrolidinas , Quinoxalinas , Sistema de Registros , Sulfonamidas
7.
Artigo em Inglês | MEDLINE | ID: mdl-35805417

RESUMO

(1) Background: Varenicline is a widely prescribed agent in smoking cessation. However, the abstinence rate, the incidence of adverse events and withdrawal symptoms, have not been widely studied locally. This study aimed to determine the prevalence of smoking abstinence, adverse events and withdrawal symptoms associated with varenicline use, as well as possible factors contributing to successful smoking abstinence. (2) Methods: This was a retrospective, cohort study conducted in twenty-two government-operated smoking cessation clinics across the state of Perak, Malaysia. The medical records of adult smokers (age ≥ 18 years old) who were prescribed with varenicline between January 2017 and June 2018 were traced. The medical records of smokers who used pharmacotherapy other than varenicline, those who received less than four weeks of varenicline treatment, and with missing data were excluded. (3) Results: Sixty-eight out of 114 subjects (59.6%) successfully achieved smoking abstinence. Probable varenicline-induced chest pain was documented in three subjects. Altered behaviour (n = 2) and auditory hallucinations (n = 1) were also reported. Varenicline treatment duration is a significant predictive factor for successful smoking abstinence (odds ratio (OR) = 2.45; 95% confidence interval (CI) 1.74-3.45; p < 0.001), followed by age (OR = 1.25; 95% CI 1.005-1.564; p = 0.045), the presence of adverse events (OR = 0.096; 95% CI 0.014-0.644; p = 0.016) and withdrawal symptoms (OR = 0.032; 95% CI 0.016-0.835; p = 0.032). (4) Conclusion: Almost two-thirds of the subjects achieved smoking abstinence with varenicline. The duration of the treatment, as well as the patients' ages had a significant influence on successful smoking abstinence. Rare cases of cardiovascular and neuropsychiatric-related adverse events were reported, warranting continuous surveillance and adverse drug reaction reporting.


Assuntos
Agonistas Nicotínicos , Síndrome de Abstinência a Substâncias , Adolescente , Adulto , Benzazepinas/efeitos adversos , Bupropiona/uso terapêutico , Estudos de Coortes , Humanos , Malásia/epidemiologia , Agonistas Nicotínicos/efeitos adversos , Quinoxalinas/efeitos adversos , Estudos Retrospectivos , Fumar , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/epidemiologia , Síndrome de Abstinência a Substâncias/etiologia , Resultado do Tratamento , Vareniclina/efeitos adversos
8.
Am J Emerg Med ; 59: 218.e5-218.e6, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35835657

RESUMO

Brimonidine is a topical ophthalmic alpha-2 adrenergic agonist solution used to treat glaucoma. The toxidrome includes drowsiness, lethargy, hypotension, bradycardia, and respiratory depression when ingested in infants. We report a case of intentional subcutaneous injection of brimonidine in an elderly patient resulting in hypotension and CNS depression that responded to naloxone. A 73-year-old female with a past medical history significant for glaucoma, hypertension, and indwelling pacemaker presented to the emergency department after injecting her brimonidine tartrate ophthalmic solution subcutaneously (SQ). The patient was not taking any antihypertensive medications or opioids. Initial presentation consisted of lethargy, a paced rhythm of 60 bpm, and blood pressure of 91/24 mmHg with a MAP of 46. Due to central nervous system depression, 3 mg of intranasal naloxone was administered. The patient was treated with intravenous fluids and escalating doses of naloxone and required a continuous infusion. Mental status and vital signs subsequently improved. The patient was admitted to the ICU and naloxone was subsequently weaned over 12 h. Systemic central alpha-2 adrenergic agonist toxicity resulted from SQ brimonidine injection. Central alpha-2 adrenergic agonist overdoses present as sympatholytic effects including CNS depression, bradycardia, hypotension, and may mimic the opioid toxidrome. Brimonidine SQ injection has not previously been reported and this case has similar findings to other central alpha-2 adrenergic agonist poisonings. Naloxone has previously shown variable reversal of CNS depression in central alpha-2 overdose. In this case, high-dose naloxone was useful for reversing CNS depression and hemodynamic instability.


Assuntos
Overdose de Drogas , Glaucoma , Hipotensão , Agonistas alfa-Adrenérgicos/uso terapêutico , Idoso , Analgésicos Opioides/uso terapêutico , Bradicardia/tratamento farmacológico , Tartarato de Brimonidina/uso terapêutico , Overdose de Drogas/tratamento farmacológico , Feminino , Glaucoma/tratamento farmacológico , Humanos , Hipotensão/tratamento farmacológico , Lactente , Injeções Subcutâneas , Letargia , Naloxona/uso terapêutico , Soluções Oftálmicas , Quinoxalinas/uso terapêutico
9.
Front Cell Infect Microbiol ; 12: 887647, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832378

RESUMO

Quinoxalines are heterocyclic compounds that contain a benzene ring and a pyrazine ring. The oxidation of both nitrogen of the pyrazine ring results in quinoxaline derivatives (QdNO), which exhibit a variety of biological properties, including antiparasitic activity. However, its activity against Entamoeba histolytica, the protozoan that causes human amebiasis, is poorly understood. Recently, our group reported that various QdNOs produce morphological changes in E. histolytica trophozoites, increase reactive oxygen species, and inhibit thioredoxin reductase activity. Notably, T-001 and T-017 derivatives were among the QdNOs with the best activity. In order to contribute to the characterization of the antiamebic effect of QdNOs, in this work we analyzed the proteomic profile of E. histolytica trophozoites treated with the QdNOs T-001 and T-017, and the results were correlated with functional assays. A total number of 163 deregulated proteins were found in trophozoites treated with T-001, and 131 in those treated with T-017. A set of 21 overexpressed and 24 under-expressed proteins was identified, which were mainly related to cytoskeleton and intracellular traffic, nucleic acid transcription, translation and binding, and redox homeostasis. Furthermore, T-001 and T-017 modified the virulence of trophozoites, since they altered their erythrophagocytosis, migration, adhesion and cytolytic capacity. Our results show that in addition to alter reactive oxygen species, and thioredoxin reductase activity, T-001 and T-017 affect essential functions related to the actin cytoskeleton, which eventually affects E. histolytica virulence and survival.


Assuntos
Entamoeba histolytica , Animais , Entamoeba histolytica/metabolismo , Humanos , Proteômica , Pirazinas , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxina Dissulfeto Redutase/farmacologia , Trofozoítos/metabolismo
10.
Molecules ; 27(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897857

RESUMO

Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-a]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABAA modulating activity) as fluorescent probes and as structural units of polymers.


Assuntos
Piridazinas , Pirazinas , Piridazinas/química , Quinoxalinas , Triazóis/química
11.
Nat Commun ; 13(1): 3815, 2022 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-35780137

RESUMO

It is highly important and challenging to develop donor-acceptor-donor structured small-molecule second near-infrared window (NIR-II) dyes with excellent properties such as water-solubility and chem/photostability. Here, we discovery an electron acceptor, 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline (TQT) with highest stability in alkaline conditions, compared with conventional NIR-II building block benzobisthiadiazole (BBT) and 6,7-diphenyl-[1,2,5] thiadiazolo[3,4-g]quinoxaline (PTQ). The sulfonated hydrophilic dye, FT-TQT, is further synthesized with 2.13-fold increased quantum yield than its counterpart FT-BBT with BBT as acceptor. FT-TQT complexed with FBS is also prepared and displays a 16-fold increase in fluorescence intensity compared to FT-TQT alone. It demonstrates real-time cerebral and tumor vessel imaging capability with µm-scale resolution. Dynamic monitoring of tumor vascular disruption after drug treatment is achieved by NIR-II fluorescent imaging. Overall, TQT is an efficient electron acceptor for designing innovative NIR-II dyes. The acceptor engineering strategy provides a promising approach to design next generation of NIR-II fluorophores which open new biomedical applications.


Assuntos
Engenharia , Neoplasias de Tecido Vascular , Corantes Fluorescentes , Humanos , Ionóforos , Oxidantes , Quinoxalinas
12.
J Infect ; 85(3): 322-326, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35700867

RESUMO

OBJECTIVES: Real world data on glecaprevir/pibrentasvir (G/P) among active drug users are scarce. We evaluated the sustained virological response (SVR) rates of G/P among individuals with and without active drug use in routine clinical practice. METHODS: Two ongoing prospective multicenter cohorts of individuals starting G/P were analyzed. Overall SVR intention-to-treat (ITT), discontinuations due to adverse effects and dropouts were evaluated. Results in patients with active, past and without active drug use were compared. RESULTS: Overall, 644 individuals started G/P and have reached the date of SVR evaluation. Of them, 613 (95.2%) individuals achieved SVR. There were two (0.3%) relapses, one (0.2%) discontinuation due to side effects and 35 (5.4%) dropouts. SVR rates for patients with active drug use, past drug use and those who never used drugs were 85.4%(n/N = 70/82), 96.1%(n/N = 320/333) and 97.4%(n/N = 223/229) respectively (p < 0.001). After adjustment by sex, age, HCV genotype and opioid agonist therapy, active drug use was the only factor independently associated with SVR (ITT) [adjusted OR (95%confidence interval): 0.29(0.09-0.99),p = 0.048]. CONCLUSIONS: Active drug use was independently associated with lower SVR rates to G/P, mainly due to voluntary dropout. G/P could be particularly beneficial in this scenario but specific strategies designed to increase the retention in care are needed.


Assuntos
Hepacivirus , Hepatite C , Ácidos Aminoisobutíricos , Antivirais/farmacologia , Benzimidazóis , Ciclopropanos , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Estudos Prospectivos , Pirrolidinas , Quinoxalinas , Sulfonamidas , Resultado do Tratamento
13.
Front Public Health ; 10: 836986, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35646774

RESUMO

Objective: This study aims to systematically review recent economic evaluations of elbasvir/grazoprevir (EBR/GZR) for chronic hepatitis C (CHC), to critically appraise the reporting quality and to summarize the results. Methods: A literature search was undertaken using Medline, Embase, the Cochrane Library, EconLit, China National Knowledge Infrastructure, Wanfang Data, and Chongqing VIP to identify original articles containing economic evaluations of EBR/GZR for CHC published between 1 January 2000 and 31 December 2020. The Consolidated Health Economic Evaluation Reporting Standards statement was used to assess the quality of reporting of the articles. Results: Of 93 articles identified, 13 studies fulfilled the inclusion criteria. These studies were conducted in 4 countries, and 8 active interventions were assessed. The target population was patients infected with CHC genotype 1 infection in all studies. Eight out of 13 studies that compared EBR/GZR vs. other direct antiviral agents suggested that EBR/GZR was generally more cost-effective or dominant than daclatasvir/asunaprevir (DCV/ASV), sofosbuvir/velpatasvir (SOF/VEL), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir (3D) but not more cost-effective than glecaprevir/pibrentasvir (GLE/PIB). Two studies from China and one study from the USA that compared EBR/GZR vs. pegylated interferon and ribavirin (PegIFN/RBV) consistently indicated that EBR/GZR was generally more cost-effective than PegIFN/RBV. One study from Italy compared EBR/GZR with SOF + PegIFN/RBV and suggested that EBR/GZR had a lower cost and higher effectiveness. One study from France and one study from the USA confirmed that compared with non-therapy for patients with chronic kidney disease, EBR/GZR was cost-effective at commonly accepted current standards. All included studies were of good quality of reporting, with an average score of 21.9 (range 19-23). Conclusion: EBR/GZR for CHC genotype 1 might be cost-effective or dominant compared with PegIFN/RBV and other direct antiviral agents (SOF/VEL, 3D, DCV/ASV, LDF/SOF) or non-therapy. However, under certain assumptions, EBR/GZR was not a cost-effective alternative for CHC patients vs. GLE/PIB.


Assuntos
Hepatite C Crônica , Amidas , Antivirais/uso terapêutico , Benzofuranos , Carbamatos , Análise Custo-Benefício , Ciclopropanos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis , Quinoxalinas , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 280: 121521, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35753100

RESUMO

Polarity is a complex parameter, with important effect in chemistry and biology. In recent years, polarity exploration attracted more and more attention hence, it's of great importance to exploit new methods for polarity determination. A novel class of long, coplanar, and amine incorporated electron-rich quinoxaline scaffold(L1) furnished maximum solvatochromic effect and large Stokes shift and was chosen to determine water content in organic solvents e.g. acetonitrile, THF, DMF, and methanol through fluorescence spectroscopy. Moreover, the probe was found to perform as an effective fluorescent sensor for the quantitative detection of low-level moisture content in four commonly-used organic solvents with low detection limits (0.018%, 0.027%, 0.012%, and 0.43% respectively). This study also describes the morphological transformation of L1 form a fibrous network to spherical aggregates upon increasing water content in several organic solvents. Real-life implementation of the probe was successfully employed for the detection of moisture content in commercial food products and building materials such as cement, sand, limestone, salt, wheat, and detergent powder. Furthermore, probe L1-immersed easy-to-prepare test strips provide a reliable approach for qualitative monitoring of water content in organic solvents by a simple color-changing method under UV irradiation via smartphone-assisted RGB analysis.


Assuntos
Aminas , Água , Corantes Fluorescentes/química , Quinoxalinas , Solventes/química , Água/química
15.
J Viral Hepat ; 29(9): 795-806, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35657133

RESUMO

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.


Assuntos
Hepatite C Crônica , Hepatite C , Amidas , Antivirais/uso terapêutico , Benzimidazóis , Benzofuranos , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Fadiga , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Quinoxalinas , Sofosbuvir/uso terapêutico , Sulfonamidas
17.
Rev Med Suisse ; 18(787): 1275-1278, 2022 Jun 22.
Artigo em Francês | MEDLINE | ID: mdl-35735153

RESUMO

Among patients suffering from schizophrenia, tobacco smoking prevalence is extremely high and represents a major burden in terms of morbidity and mortality. Tobacco smoking is under-diagnosed and under-treated by mental health professionals, mostly due to an overestimated risk of jeopardizing the patient's mental condition, but also due to a lack of expertise on tobacco cessation treatment. Despite the extent of this problem, pharmacological approaches haven't been studied enough. However, treatments such as varenicline, bupropion and nicotine replacement are effective and well tolerated and their prescription should be recommended for tobacco withdrawal among these patients.


La prévalence du tabagisme chez les patients souffrant de schizophrénie est extrêmement élevée et il constitue une charge majeure de morbidité et mortalité pour ces patients. Cependant, cette problématique reste sous-diagnostiquée et sous-traitée par les professionnels de santé mentale, notamment en raison d'une surestimation du risque de décompensation du trouble psychiatrique et par manque de compétences dans le domaine de la tabacologie. Malgré l'ampleur de la problématique, les approches pharmacologiques ont été peu étudiées pour cette population. Néanmoins, la prescription de traitements comme la varénicline, le bupropion et la substitution en nicotine, qui sont bien tolérés et efficaces, est recommandée pour l'aide au sevrage tabagique chez ces patients.


Assuntos
Esquizofrenia , Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Benzazepinas/efeitos adversos , Bupropiona/uso terapêutico , Humanos , Nicotina/efeitos adversos , Quinoxalinas/efeitos adversos , Esquizofrenia/epidemiologia , Esquizofrenia/terapia , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêutico
18.
J Agric Food Chem ; 70(23): 7029-7038, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35649047

RESUMO

Quinoxaline and its derivatives are important functional molecules with a broad range of applications. Disclosed here is a design and synthesis of a series of novel quinoxaline derivatives containing dithioacetal moieties as well as their antiviral activities against potato virus Y (PVY). The compound D30 was developed on the basis of the three-dimensional quantitative structure-activity relationship. The anti-PVY activity test showed that the half maximal effective concentration of the anti-PVY protective activity of compound D30 is 197 µg/mL, which was better than the control agents ningnanmycin (423 µg/mL) and xiangcaoliusuobingmi (281 µg/mL). Significantly, compound D30 can increase defense enzyme activity and chlorophyll content, promote photosynthesis by accelerating carbon fixation in tobacco, and further improve plant disease resistance. All of these results suggest that compound D30 could be employed as a lead compound for novel PVY inhibitor discovery.


Assuntos
Potyvirus , Vírus do Mosaico do Tabaco , Antivirais/farmacologia , Resistência à Doença , Doenças das Plantas , Quinoxalinas/farmacologia , Tabaco
19.
Bioorg Chem ; 126: 105860, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35661525

RESUMO

Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo[1,2-a]quinoxalin-4(5H)-one and imidazo[1,2-a]quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.


Assuntos
Inibidores de Proteínas Quinases , Quinoxalinas , Tirosina Quinase da Agamaglobulinemia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
20.
Chem Commun (Camb) ; 58(54): 7554-7557, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35708006

RESUMO

The selectivity and efficiency of benzene and toluene uptake at the gas-solid interface by quinoxaline cavitands is strongly enhanced by partial rigidification of the receptor cavity and immobilization of the cavitand onto silica gel particles.


Assuntos
Éteres Cíclicos , Quinoxalinas , Conformação Molecular , Resorcinóis
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