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1.
J Anesth Hist ; 7(1): 11-16, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34120709

RESUMO

BACKGROUND: Within the history of intravenous anesthesia, barbiturates represent a chapter of considerable importance. Although the reference barbiturate thiopental had several limitations, it dominated the scene of the intravenous anesthesia until the mid-1980s, when propofol was introduced on the market. In the meantime, several barbiturate derivatives were placed on the market and abounded. This work is aimed at evaluating the clinical impact of the barbiturate derivatives methitural, analyzing the reasons for its rapid abandonment, in the late 1950s. METHODS: A systematic methodology of the search was associated with a descriptive analysis of the bibliography found. A computer-operated search strategy using Medline and Google Scholar databases was implemented. The algorithm was composed by using the words "Diogenal" OR "Thiogenal" OR "Methitural" OR "Metigenal" OR "Neraval" including biochemical and marketed terms. A manual search of the sources was carried out, and precise inclusion and exclusion criteria were established. The narrative synthesis was conducted taken into account the historical context of anesthesia. RESULTS: The database search yielded 3645 records. Nineteen records were identified through other sources. After duplicates removing (n = 238), and exclusion of not pertinent 3027 records, 314 full-text articles were assessed for eligibility. Of those, other 225 papers were excluded and 89 articles were included in the qualitative synthesis. CONCLUSION: Although methitural could be useful in particular surgical settings such as short-acting surgery, and in patients with liver diseases, a limited advantage over thiopental, and its scarce market diffusion due to increased costs, have limited its use. Through a critical analysis of literature, the lack of high-quality studies does not allow us to draw definitive conclusions on the drug.


Assuntos
Anestesia Intravenosa/história , Anestesiologia/história , Anestésicos Intravenosos/história , Tiobarbitúricos/história , Alemanha , História do Século XX
2.
Anticancer Res ; 41(3): 1171-1181, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788708

RESUMO

BACKGROUND/AIM: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma. MATERIALS AND METHODS: The biological activity of CC-I on drug-resistant neuroblastomas [e.g., HFE gene variant C282Y stably transfected human neuroblastoma SH-SY5Y cells (C282Y HFE/SH-SY5Y), SK-N-AS] was characterized using cell culture models and in vivo mouse tumor models. RESULTS: CC-I had potent cytotoxicity on therapy-resistant neuroblastoma cells and limited cytotoxicity on human primary dermal fibroblast cells. In addition, CC-I showed a robust anti-tumor effect on therapy-resistant human neuroblastoma C282Y HFE/SH-SY5Y cells but not on SK-N-AS cells in a subcutaneous tumor model. CC-I induced phosphorylation of heat shock protein 27 (HSP27), protein kinase B (Akt), and c-Jun N-terminal kinase (JNK) in C282Y HFE/SH-SY5Y neuroblastoma cells. CONCLUSION: CC-I may be an effective therapeutic option for therapy-resistant neuroblastomas, especially if they express the C282Y HFE gene variant. Its anti-tumor effects are possibly through HSP27-Akt-JNK activation.


Assuntos
Antineoplásicos/farmacologia , Neuroblastoma/tratamento farmacológico , Tiobarbitúricos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Fibroblastos/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/fisiologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Masculino , Camundongos , Neuroblastoma/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Tiobarbitúricos/uso terapêutico
3.
Bioorg Med Chem Lett ; 40: 127922, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705910

RESUMO

A ferrocene-substituted thiobarbituric acid (FT) has been synthesized to explore its photophysical properties and photodynamic and photoantimicrobial chemotherapy activities. FT has an intense metal-to-ligand charge transfer (MLCT) band at ca. 575 nm. The ferrocene moiety of FT undergoes photooxidation to form a ferrocenium species which in turn produces hydroxyl radical in an aqueous environment, which was confirmed via the bleaching reaction of p-nitrosodimethylaniline (RNO). FT exhibits efficient PDT activity against MCF-7 cancer cells with an IC50 value of 5.6 µM upon irradiation with 595 nm for 30 min with a Thorlabs M595L3 LED (240 mW cm-2). Photodynamic inactivation of Staphylococcus aureus and Escherichia coli by FT shows significant activity with log reduction values of 6.62 and 6.16 respectively, under illumination for 60 min at 595 nm. These results demonstrate that ferrocene-substituted thiobarbituric acids merit further study for developing novel bioorganometallic PDT agents.


Assuntos
Antibacterianos/farmacologia , Compostos Ferrosos/farmacologia , Metalocenos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Tiobarbitúricos/farmacologia , Antibacterianos/química , Antibacterianos/efeitos da radiação , Escherichia coli/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Ferrosos/efeitos da radiação , História Medieval , Humanos , Radical Hidroxila/metabolismo , Luz , Células MCF-7 , Metalocenos/química , Metalocenos/efeitos da radiação , Testes de Sensibilidade Microbiana , Oxirredução/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Staphylococcus aureus/efeitos dos fármacos , Tiobarbitúricos/química , Tiobarbitúricos/efeitos da radiação
4.
Molecules ; 26(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494519

RESUMO

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure-activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3-6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure-activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II , Simulação de Acoplamento Molecular , Proteínas de Neoplasias , Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose , Tiobarbitúricos , Inibidores da Topoisomerase II , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Feminino , Humanos , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Tiobarbitúricos/síntese química , Tiobarbitúricos/química , Tiobarbitúricos/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
5.
J Appl Microbiol ; 130(5): 1671-1683, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32979295

RESUMO

AIM: In this work, we evaluated the effects of light on growth, cell physiology and stress response of Azospirillum brasilense Az39, a non-photosynthetic rhizobacteria, under planktonic growth conditions. METHODS AND RESULTS: Exponential cultures of Az39 were exposed to blue (BL), red (RL) and daylight (DL) or maintained in darkness for 24, 48 and 72 h. The biomass production and indole 3-acetic acid (IAA) biosynthesis increased by exposition to DL. Conversely, BL decreased IAA concentration through a direct effect on the molecule. The DL increased superoxide dismutase activity, hydrogen peroxide and thiobarbituric acid reactive substances levels, but the last one was also increased by BL. Both DL and BL increased cell aggregation but only BL increased biofilm formation. CONCLUSIONS: We demonstrated that both BL and DL are stress effectors for A. brasilense Az39 under planktonic growth conditions. The DL increased biomass production, IAA biosynthesis and bacterial response to stress, whereas BL induced cell aggregation and biofilms formation, but decreased the IAA concentration by photooxidation. SIGNIFICANCE AND IMPACT OF THE STUDY: Blue light and DL changes growth capacity, cell physiology and plant growth promotion ability of A. brasilense Az39 and these changes could be considered to improve the production and functionality of biofertilizers.


Assuntos
Azospirillum brasilense/fisiologia , Peróxido de Hidrogênio/metabolismo , Ácidos Indolacéticos/metabolismo , Luz , Superóxido Dismutase/metabolismo , Tiobarbitúricos/metabolismo , Azospirillum brasilense/efeitos da radiação , Proteínas de Bactérias/metabolismo , Biofilmes , Sobrevivência Celular , Escuridão , Estresse Fisiológico
6.
Photodiagnosis Photodyn Ther ; 33: 102102, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33212264

RESUMO

Two thiobarbituric acid-functionalized pyrene derivatives (P1, P2) have been synthesized to explore the photophysical properties and photodynamic activity of dyes of this type. Both compounds exhibit an intense intramolecular charge transfer (ICT) band at ca. 470 nm, which is absent in the spectra of the precursor. P1 and P2 exhibit singlet oxygen generation on irradiation with light with moderate singlet oxygen yields of 0.36 and 0.32, respectively, in DMSO. P1 showed better photodynamic activity against MCF-7 cells with an IC50 value of 18.3 µM under illumination at 455 nm for 60 min with a Thorlabs M455L3 LED (330 mW.cm-2).


Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Células MCF-7 , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Pirenos , Oxigênio Singlete , Tiobarbitúricos
7.
Biophys Chem ; 269: 106522, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352334

RESUMO

Neurodegenerative disease is caused by the abnormal build-up of proteins in and around cells called amyloid. The amyloid fibril formation and its mechanism have been investigated with various techniques, including dye-binding assay. Thioflavin T (ThT) has been one of the most widely used dyes for quantifying amyloid deposits, but ThT has a weak fluorescence signal especially at low concentration of amyloid fibrils, low lipophilicity and positive charge that makes it unable to cross the blood-brain barrier (BBB) to detect amyloid fibrils in vivo. Hence, there is a strong motivation for designing and developing the new compounds for in vitro amyloid quantification and in vivo amyloid imaging. The need for new probes to detect amyloid fibrils, especially within the cell, is highlighted by the fact that an accurate understanding of the molecular details of amyloid fibril formation is required to design and develop strategies for controlling the amyloid formation, and this needs more reliable probes for amyloid identification. In this work, we synthesized and applied barbituric and thiobarbituric acid-based chromene derivatives, as new fluorescent dyes to quantitatively detect the amyloid fibrils of bovine serum albumin (BSA) and human insulin in comparison with native soluble proteins or amorphous aggregation. Our results showed that among the 14 synthesized compounds, five compounds 4a, 4h, 4j, 4k, and 4l could selectively and specifically bind to amyloid fibrils while other compounds demonstrated a low-affinity binding. Furthermore, according to the cell viability experiment, compounds 4a, 4j and 4l at low concentration of compounds are not toxic, especially compound 4j which could be used as a suitable candidate for in vivo study. Further studies are needed to determine all the properties of compounds, especially in vivo experiments.


Assuntos
Amiloide/química , Barbitúricos/química , Benzopiranos/química , Benzopiranos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Tiobarbitúricos/química , Animais , Benzopiranos/síntese química , Técnicas de Química Sintética
8.
Molecules ; 25(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287099

RESUMO

This research was conducted in order to establish the effectiveness of two freeze-dried extracts obtained from blueberry processing byproducts resulting from juice manufacturing compared to butylated hydroxytoluene (BHT) in delaying the lipid oxidation of sunflower oil subjected to high-temperature convective heating at 180 °C up to 12 h under simulated frying conditions. The fruits were harvested from spontaneous flora of two regions of Romania, Arieseni (Alba County) and Paltinis (Sibiu County) and the blueberry byproducts extracts (BBE) were noted according to the origin place as ABBE and PBBE. The progress of lipid thermo-oxidation was investigated in terms of peroxide value (PV), p-anisidine value (p-AV), the response of TBA-malondialdehyde interactions assessed by thiobarbituric acid (TBA) method, the total oxidation (TOTOX) value and inhibition of oil oxidation (IO). The recorded data highlighted that BBE exhibit a high inhibitory response on lipid thermo-oxidation. The inhibitory effect was concentration-dependent, thus, the degree of lipid oxidation was in reverse related to the BBE dose. The exposure of the oil samples supplemented with 800 ppm BBE (ABBE, PBBE) to a high-temperature heating for 12 h led to a significant decrease of the assessed indices compared to additives-free sunflower oil sample as follows: PV (46%; 45%), p-AV (21%; 17%), TOTOX (27%; 24%), TBA value (25%; 11%). Regarding the impact of the origin on the potential of BBE to inhibit the lipid oxidative degradation, it was noted that ABBE derived from blueberries grown in a region with a milder climate with moderate precipitations and higher temperatures showed a stronger inhibitory effect on lipid thermo-oxidation than PBBE. A moderate level of 500 ppm BBE inhibited the lipid oxidation similar to 200 ppm BHT. The reported results reveal that BBE represent efficient natural antioxidants that could be successfully applied to improve the thermo-oxidative stability of sunflower oil used in various high-temperature food applications.


Assuntos
Antioxidantes/química , Mirtilos Azuis (Planta)/química , Frutas/química , Óleo de Girassol/química , Compostos de Anilina/química , Hidroxitolueno Butilado/química , Temperatura Alta , Malondialdeído/química , Oxirredução/efeitos dos fármacos , Extratos Vegetais/química , Romênia , Tiobarbitúricos/química
9.
Mol Vis ; 26: 722-730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33209015

RESUMO

Purpose: Central serous chorioretinopathy (CSCR) has been associated with oxidative stress-related risk factors. The objective of this study was to optimize an analytical method for evaluating the oxidative stress biomarker malondialdehyde (MDA) in human tears and determine its level in the tears of patients with CSCR. Methods: In this pilot study, tear samples were obtained from 34 healthy donors and 31 treatment-naïve CSCR male patients (eight with acute CSCR and 23 with chronic CSCR). Two analytical methods based on high-performance liquid chromatography followed by fluorescence detection were evaluated, with either 2-thiobarbituric derivative (TBA) or 2-aminoacridone (2-AA). Activity of CSCR was defined by the serous retinal detachment (SRD) height, which was measured by two independent observers on spectral-domain optical coherence tomography. Results: The 2-AA method showed higher sensitivity and precision compared to the TBA method. When the 2-AA method was applied to tears from healthy donors, the levels of MDA were statistically significantly higher in men compared to women (mean ± standard deviation, SD: 9,914 nM ± 6,126 versus 4,635 nM ± 1,173, p = 0.006). No difference was found in tear MDA levels between male patients with CSCR and age-matched control men (p = 0.17). However, MDA levels were statistically significantly higher in acute compared to chronic CSCR cases (mean ± SD: 12,295 nM ± 8,495 versus 6,790 ± 3,969 nM, p = 0.03). Additionally, there was a correlation between MDA levels and RPE leakage, quantified by the height of the serous retinal detachment (p = 0.02, r = 0.40). Conclusions: Levels of MDA in tears, measured with an optimized analytical method, correlate with RPE leakage in CSCR.


Assuntos
Coriorretinopatia Serosa Central/metabolismo , Coriorretinopatia Serosa Central/patologia , Malondialdeído/metabolismo , Estresse Oxidativo , Lágrimas/metabolismo , Adulto , Aminoacridinas/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Coriorretinopatia Serosa Central/complicações , Coriorretinopatia Serosa Central/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Descolamento Retiniano/complicações , Descolamento Retiniano/diagnóstico por imagem , Tiobarbitúricos/metabolismo , Tomografia de Coerência Óptica
10.
Anticancer Res ; 40(11): 6039-6049, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109542

RESUMO

BACKGROUND/AIM: Previously, we reported the identification of a cytotoxic chemotype compound CC-I (1a), a derivative of thiobarbituric acid. We also reported the anticancer activity of a series of novel thio- and seleno-barbituric acid analogs. MATERIALS AND METHODS: We herein evaluated the effect of 1a and its modified compounds on in vitro and in vivo lung cancer models. RESULTS: The compounds 1b and 2a showed more potent cytotoxicity than 1a to lung cancer cells. Moreover, 1b did not have any cytotoxicity on normal cells, such as fibroblasts. In the human lung cancer A549 mouse tumor xenograft model, 1b and 2a showed more pronounced antitumor effects than 1a In the A549 lung cancer cells, 1a induced cell death mainly via JNK and p38 MAPK activation. However, compound 1b and 2a induced lung cancer cell death mostly through JNK activation. CONCLUSION: The results suggest that 1b and 2a can be useful therapeutic agents for lung cancer.


Assuntos
Barbitúricos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Tiobarbitúricos/uso terapêutico , Células A549 , Barbitúricos/síntese química , Barbitúricos/química , Barbitúricos/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Tiobarbitúricos/química , Tiobarbitúricos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Bioorg Med Chem ; 28(23): 115759, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32992246

RESUMO

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.


Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/química , Tiobarbitúricos/química , Urease/antagonistas & inibidores , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Concentração de Íons de Hidrogênio , Marcação por Isótopo , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Compostos de Organotecnécio/química , Proteus vulgaris/efeitos dos fármacos , Relação Estrutura-Atividade , Tiobarbitúricos/metabolismo , Tiobarbitúricos/farmacologia , Tioureia/análogos & derivados , Tioureia/metabolismo , Tioureia/farmacologia , Distribuição Tecidual , Urease/metabolismo
12.
J Enzyme Inhib Med Chem ; 35(1): 1781-1799, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32975138

RESUMO

The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.


Assuntos
Antineoplásicos/química , DNA Topoisomerases/metabolismo , Inibidores da Topoisomerase/química , Acridinas/química , Acridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Dexrazoxano/química , Dexrazoxano/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Quinolonas/química , Quinolonas/farmacologia , Relação Estrutura-Atividade , Tiobarbitúricos/química , Tiobarbitúricos/farmacologia , Inibidores da Topoisomerase/farmacologia
13.
Molecules ; 25(13)2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640700

RESUMO

Xanthine oxidase is a frontier enzyme to produce oxidants, which leads to inflammation in the blood. Prenylated isoflavones from Flemingia philippinensis were found to display potent inhibition against xanthine oxidase (XO). All isolates (1-9) inhibited XO enzyme with IC50 ranging 7.8~36.4 µM. The most active isoflavones (2-5, IC50 = 7.8~14.8 µM) have the structural feature of a catechol motif in B-ring. Inhibitory behaviors were disclosed as a mixed type I mode of inhibition with KI < KIS. Binding affinities to XO enzyme were evaluated. Fluorescence quenching effects agreed with inhibitory potencies (IC50s). The compounds (2-5) also showed potent anti-LDL oxidation effects in the thiobarbituric acid-reactive substances (TBARS) assay, the lag time of conjugated diene formation, relative electrophoretic mobility (REM), and fragmentation of apoB-100 on copper-mediated LDL oxidation. The compound 4 protected LDL oxidation with 0.7 µM in TBARS assay, which was 40-fold more active than genistein (IC50 = 30.4 µM).


Assuntos
Fabaceae/química , Isoflavonas/análise , Isoflavonas/farmacologia , Lipoproteínas LDL/metabolismo , Raízes de Plantas/química , Tiobarbitúricos/química , Xantina Oxidase/antagonistas & inibidores , Cromatografia Líquida , Cobre/química , Inibidores Enzimáticos/química , Fluorescência , Concentração Inibidora 50 , Isoflavonas/química , Isoflavonas/isolamento & purificação , Cinética , Espectrometria de Massas , Oxirredução , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Prenilação , Xantina Oxidase/metabolismo
14.
Comput Biol Chem ; 88: 107318, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32622179

RESUMO

The inhibition of GABAA can be used in general anesthesia. Although, barbiturates and thiobarbiturates are used in anesthesia, the mechanism of their action hasn't been established. QSAR modeling is a wieldy used technique in these cases and this study presents the QSAR modeling for a group of barbiturates and thiobarbiturates with determined anesthetic activity. Developed QSAR models were based on conformation independent and 2D descriptors as well as field contribution. As descriptors used for developing conformation independent QSAR models, (SMILES) notation and local invariants of the molecular graph were used. Monte Carlo optimization method was applied for building QSAR models for two defined activities. Methodology for developing QSAR models capable of dealing with the small dataset that integrates dataset curation, "exhaustive" double cross-validation and a set of optimal model selection techniques including consensus predictions was used. Two-dimensional descriptors with definite physicochemical meaning were used and modeling was done with the application of both partial least squares and multiple linear regression models with three latent variables related to simple and interpretable 2D descriptors. Different statistical methods, including novel method - the index of ideality of correlation, were used to test the quality of the developed models, especially robustness and predictability and all obtained results were good. In this study, obtained results indicate that there is a very good correlation between all developed models. Molecular fragments that account for the increase/decrease of a studied activity were defined and further used for the computer-aided design of new compounds as potential anesthetics.


Assuntos
Anestésicos/farmacologia , Barbitúricos/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores de GABA-A/metabolismo , Tiobarbitúricos/farmacologia , Anestésicos/química , Barbitúricos/química , Antagonistas de Receptores de GABA-A/química , Humanos , Modelos Moleculares , Estrutura Molecular , Tiobarbitúricos/química
15.
Arch Pharm (Weinheim) ; 353(9): e2000023, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32596826

RESUMO

A new series of 1,2,3-triazole-(thio)barbituric acid hybrids 8a-n was designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated against Helicobacter pylori urease. The obtained result demonstrated that all the synthesized compounds, 8a-n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds 8a, 8c-e, 8g,h, and 8k,l exhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds, 8e and 8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds 8a-n predicted that all these compounds can be orally active. The ADME prediction of compounds 8a-n was also performed.


Assuntos
Inibidores Enzimáticos/farmacologia , Tiobarbitúricos/farmacologia , Triazóis/farmacologia , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tiobarbitúricos/síntese química , Tiobarbitúricos/química , Tioureia/farmacologia , Triazóis/síntese química , Triazóis/química
16.
Mol Neurobiol ; 57(7): 3014-3026, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458388

RESUMO

Oxidative stress associated with chronic cerebral hypoperfusion is one of the fundamental factors leading to neurodegenerative diseases. To prevent oxidative stress, physical activity is effective. Physical exercise enables development of rehabilitation techniques that can progressively increase patients' stress resistance. We determined the oxidative stress dynamics in experimental hypoperfusion and modeled rehabilitation measures, comparing sex and stress resistance levels. The experiment was performed on 240 Wistar rats of both sexes over a period of 90 days. Based on behavioral test results obtained using the open field test, the rats were divided into active animals with predicted higher stress resistance (HSR) and passive animals with predicted lower stress resistance (LSR). TBA (thiobarbituric acid) plasma concentration of the active products (malondialdehyde-MDA), blood plasma (NO-X) concentration, and L-citrulline (LC) concentration were determined spectrophotometrically at the corresponding wave length (nm). The intensity of oxidative stress was evaluated using the chemoluminscent method to determine the blood plasma antioxidant activity on the BCL-07 biochemoluminometer. This study revealed two stages of oxidative stress: a less pronounced phase covering the first days after surgery and a main one, which starts from the month after the operation to 3 months. Female sex and a high initial level of stress resistance reduced the severity of oxidative stress. Physical activity commencing a week after the surgery resulted in "reloading" the adaptive mechanisms and slowed the onset of the main stage, leading to a decrease in the free-radical process in all studied subgroups and the greater blood plasma (NO)-X decrease in the male animals. Future neuropharmacological intervention most likely will be able to determine the pathophysiology mechanism of chronic brain hypoperfusion and potentially extending adaptive responses.


Assuntos
Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Estresse Psicológico/metabolismo , Animais , Feminino , Masculino , Malondialdeído/sangue , Aprendizagem em Labirinto/fisiologia , Ratos Wistar , Fatores Sexuais , Tiobarbitúricos/sangue
17.
Talanta ; 214: 120842, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278426

RESUMO

Hypochlorite (ClO-) could be used as a diagnostic marker for inflammation and related diseases. Although there have been many reports on probes for ClO- imaging, there was still a lack of specificity and anti-interference ability. Herein, carbazole (NEC) and tetraphenylethylene (TPE) equipped with thiobarbituric acid (TBA), NEC-TBA and TPE-TBA, were synthesized and used as a fluorescence biosensor for monitoring ClO- with aggregation-induced emission (AIE) effect. we identified that TPE-TBA, with formed nanoparticles in the mean grain size at 76 nm (5 µM), was a superior probe to target ClO- over other analytes with fluorescence "turn off" strategy. Subsequently, to explore the bioimaging application, TPE-TBA was able to sense exogenous ClO- in living HeLa cells through fluorescence imaging. In zebrafish model, TPE-TBA effectively captured exogenous ClO- in the entire organization of zebrafish. Overall, these AIE-based probes merit further development as organism targeting ClO- sensors.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Nanopartículas/química , Imagem Óptica , Animais , Técnicas Biossensoriais , Carbazóis/química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Estrutura Molecular , Tamanho da Partícula , Espectrometria de Fluorescência , Estilbenos/química , Propriedades de Superfície , Tiobarbitúricos/química , Células Tumorais Cultivadas , Peixe-Zebra
18.
J Enzyme Inhib Med Chem ; 35(1): 692-701, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32156165

RESUMO

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a-k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM).


Assuntos
Aminas/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Tiobarbitúricos/farmacologia , alfa-Glucosidases/metabolismo , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Glicosilação/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiobarbitúricos/síntese química , Tiobarbitúricos/química
19.
Molecules ; 25(4)2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32079080

RESUMO

In the last decade, there has been growing interest in the food industry in replacing synthetic chemicals with natural products with bioactive properties. This study's aims were to determine the chemical composition and the antioxidant properties of the essential oil of Pastianica sylvestris. The essential oil was isolated with a yield of 0.41% (w/v) by steam distillation from the dried seeds and subsequently analysed by GC-MS. Octyl acetate (78.49%) and octyl hexanoate (6.68%) were the main components. The essential oil exhibited an excellent activity for the inhibition of primary and secondary oxidation products for cold-pressed sunflower oil comparable with butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), which were evaluated using peroxide and thiobarbituric acid values. The antioxidant activity of the essential oil was additionally validated using DPPH radical scavenging (0.0016 ± 0.0885 mg/mL), and ß-carotene-linoleic acid bleaching assays. Also, the amounts of total phenol components (0.0053 ± 0.0023 mg GAE/g) were determined.


Assuntos
Acetatos/química , Antioxidantes/química , Óleos Voláteis/química , Pastinaca/química , Sementes/química , Acetatos/isolamento & purificação , Antioxidantes/isolamento & purificação , Bioensaio , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Hidroxianisol Butilado/química , Hidroxianisol Butilado/isolamento & purificação , Hidroxitolueno Butilado/química , Cromatografia Gasosa-Espectrometria de Massas , Ácido Linoleico/química , Óleos Voláteis/isolamento & purificação , Fenóis/química , Picratos/antagonistas & inibidores , Picratos/química , Extratos Vegetais/química , Óleo de Girassol/química , Tiobarbitúricos/química , beta Caroteno/química
20.
Medicina (Kaunas) ; 56(2)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054000

RESUMO

BACKGROUND AND OBJECTIVES: The purpose of this study is to evaluate the level of oxidative stress before and after breast cancer surgery. MATERIALS AND METHODS: Malondialdehyde (MDA) level was tested using a thiobarbituric acid (TBA) assay based on the release of a color complex due to TBA reaction with MDA. The glutathione S-transferase (GST) activity was evaluated by enzymatic conjugation of reduced glutathione (GSH) with 1-chloro-2,4-dinitrobenzene. The level of total glutathione (reduced GSH and oxidized GSSG) was detected using a recycling system by 5,5-dithiobis(2-nitrobenzoic acid). The levels of the indices were determined in the serum of 52 patients before surgery, two hours and five days after surgery, and in 42 healthy women. RESULTS: In the patients over 50 years old the level of MDA was higher after surgery in comparison with before surgery, and GST activity was lower in comparison with the control. The GSH + GSSG level in both ages groups after surgery was lower than in the control. Significant differences of MDA level were detected in patients with stage III after surgery compared to the control. The level of GSH + GSSG was significantly lower in the patients with I-III stages compared to the control. CONCLUSION: The most expressed changes demonstrate the significance of MDA as a marker to evaluate oxidative stress in breast cancer patients. The degree of oxidative stress depends on the patient's age and stage of disease.


Assuntos
Antioxidantes/análise , Neoplasias da Mama/sangue , Oxidantes/sangue , Período Pós-Operatório , Período Pré-Operatório , Adulto , Feminino , Glutationa Transferase/análise , Glutationa Transferase/sangue , Humanos , Malondialdeído/análise , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo , Tiobarbitúricos/análise , Tiobarbitúricos/sangue
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