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1.
J Agric Food Chem ; 71(1): 255-266, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36583683

RESUMO

Concerned about weed infestation, a major threat to food production and herbicide resistance that interferes in the mechanism of action of the main herbicides, we have synthesized eight isatin derivatives using the "Click Chemistry" approach through copper-catalyzed azide-alkyne cycloadditions (CuAAC). Sixteen isatin derivatives were evaluated for their phytotoxic activity against the seed culture of the model plants, Lactuca sativa and Allium cepa. Six of them showed phytotoxic activity similar to the positive control, trifluralin. Hypocotyl length measurement analysis in L. sativa revealed that triazole derivative 8 is more active than trifluralin. For A. cepa, root length measurement analyses revealed that 3, 10, 14, 16, and 17 were similar to the positive control trifluralin. Three-dimensional quantitative structure-activity relationship (3D-QSAR) comparative molecular field analysis (CoMFA) model construction using the acetolactate synthase (ALS) crystallographic structure displayed pki values of predicted inhibitory activity and contour maps revealing sterically bulky groups for 11, the CF3 group in ortho, and for 17, Br in ortho, favoring the inhibitory ALS activity.


Assuntos
Herbicidas , Isatina , Relação Quantitativa Estrutura-Atividade , Isatina/farmacologia , Trifluralina , Herbicidas/química
2.
Biochimie ; 194: 43-50, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34952193

RESUMO

Diabetes is a metabolic disorder that presents hyperglycemia and vascular complications due to the non-production of insulin or its inappropriate use by the body. One of the strategies to treat diabetes is the inhibition of dipeptidyl peptidase-4 (DPP-4) and it is interesting to conduct virtual screening studies to search for new inhibitors of the DPP-4 enzyme. This study involves a virtual screening using the crystallographic structure of DPP-4 and a compound subset from the ZINC database. To filter this compound subset, we used some physicochemical properties, positioning at the three DPP-4 binding sites, molecular interactions, and ADME-Tox properties. The conformations of ligands obtained from AutoDock Vina were analyzed using a consensus with other algorithms (AutoDock and GOLD). The compounds selected from virtual screening were submitted to biological assays using the "DPPIV-Glo™ protease assay". Cytotoxicity tests were also performed. One promising compound (ZINC1572309) established interactions with important residues at the binding site. The results of the ADME-Tox prediction for ZINC1572309 were compared with a reference drug (sitagliptin). The cytotoxicity of sitagliptin and ZINC1572309 were evaluated using the XTT short-term cytotoxic assay, including normal and tumor cell lines to observe the cellular response to inhibitor treatment at different genetic bases. Both compounds (ZINC1572309 and the reference drug - sitagliptin) also inhibited DPP-4 activity, suggesting interesting biological effects of the selected compound at non-cytotoxic concentrations. Therefore, from in silico and in vitro studies, a potential hit as DPP-4 inhibitor was discovered and it can be structurally optimized to achieve suitable activity and pharmacokinetic profiles.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Sítios de Ligação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Ligantes , Fosfato de Sitagliptina
3.
J Mol Model ; 27(9): 239, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34363097

RESUMO

Protein kinases (in this case, HER-2 and EGFR) are involved in cancer-related diseases. Some reports have shown unique CoMFA models using the sum of activities expressed as pIC50 (-log IC50), as the classical CoMFA technique would not be the best strategy to construct models for multitarget therapy considering that the molecular alignment will not be the same for different targets. An alternative for this problem is the use of Topomer-CoMFA, a variation of CoMFA, which does not require the alignment step in the generation of 3D models. In this study, we propose the combined use of the sum of activities and Topomer-CoMFA for the construction of a unique dual 3D model considering the inhibitory activities against EGFR and HER-2. For this, 88 compounds from the literature were divided into two groups: training (71) and test (17) sets. The biological activity of each compound, expressed as IC50 for EGFR and HER-2, was transformed into pIC50, summed, and used as the dependent variable in the Topomer-CoMFA analyses. The obtained model was considered statistically robust in the prediction of the dual activity of new compounds. Finally, based on the obtained model, we proposed structural modifications to some of the compounds used to improve the biological data. From the 3D model, we suggested new derivative compounds with improved biological activity for both targets. Therefore, the combination of the techniques proposed in this study proves to be a good strategy to construct better statistical models that can predict biological activities in multitarget systems.


Assuntos
Modelos Moleculares , Inibidores de Proteínas Quinases/química , Receptor ErbB-2 , Software , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Humanos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/química
4.
Curr Top Med Chem ; 21(22): 1999-2017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225623

RESUMO

BACKGROUND: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. OBJECTIVE: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. METHODS: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. RESULTS: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). CONCLUSION: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.


Assuntos
Flavonoides/síntese química , Flavonoides/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia
5.
Community Ment Health J ; 56(7): 1292-1297, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32451795

RESUMO

This study aimed to investigate the risk factors for depressive symptoms among rural residents in Brazil. A representative sample of two hundred eighty-eight volunteers aged from 18 to 65 years was included and determining factors for high BDI-II score were investigated through a multivariate logistic model. Sadness, loss of pleasure, crying, worthlessness and loss of interest in sex are more likely to be observed in females, and risk factors to this high depression score among rural residents were shown to be: female gender, tobacco use, pesticide application, poor self-perceived health and presence of chronic disease. These data contribute to the knowledge of factors determining depressive symptoms among rural residents and may help to expand health policies to improve quality of rural life on these communities and others with similar characteristics.


Assuntos
Depressão , População Rural , Brasil/epidemiologia , Depressão/epidemiologia , Feminino , Humanos , Fatores de Risco , Uso de Tabaco
6.
Curr Top Med Chem ; 20(2): 153-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31648640

RESUMO

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3ß isoforms is likely to represent an effective strategy against AD. OBJECTIVE: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3ß kinase inhibitors. METHODS: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3ß activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3ß complex [Protein Data Bank (PDB) code: 1Q3D]. RESULTS: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3ß inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3ß enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. CONCLUSION: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3ß inhibitors.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Cumarínicos/química , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 19(12)2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477154

RESUMO

HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r² calibration = 0.98 and q²cv = 0.83) and EGFR (r² calibration = 0.98 and q²cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r² calibration = 0.92 and q²cv = 0.74) and EGFR (r² calibration = 0.97 and q²cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer.


Assuntos
Desenho de Fármacos , Receptores ErbB/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Receptores ErbB/antagonistas & inibidores , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Reprodutibilidade dos Testes
8.
PLoS One ; 13(7): e0197699, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30063700

RESUMO

OBJECTIVE: To assess the association between indicators of psychosocial stress and central adiposity in adult users of the Unified Health System (SUS) from Southeast of Brazil. METHODS: This cross-sectional study was conducted with 384 adults (20 to 59 years old) from the city of Alegre, Southeastern Brazil. The simple random sample represented the population using the public health system of the municipality. The prevalence of obesity was based on the Body Mass Index, and central adiposity (dependent variable) was measured by waist circumference in centimeters. The independent variables were the following indicators of psychosocial stress: food and nutrition insecurity (yes/no), serum cortisol (µg/dL), symptoms suggestive of depression using the Beck Depression Inventory-II ≥ 17 (yes/no), and altered blood pressure ≥ 130/85 mmHg (yes/no). Univariate linear regression was performed between central adiposity and each stress indicator, and later the models were adjusted for socioeconomic, health, and lifestyle variables. All analyses were made separately by rural and urban location. RESULTS: The prevalence of weight excess, by the classification of the Body Mass Index ≥ 25.0 kg/m2, was 68.3% and, by waist circumference, 71.5% of individuals presented an increased risk for metabolic complications related to central adiposity. Mean waist circumference scores for the rural and urban population were 89.3 ± 12.7 cm and 92.9 ± 14.7 cm, respectively (p = 0.012). Indicators of stress that were associated with central adiposity were: cortisol in the rural population (ß = -0.60; 95% CI = -1.09;-0.11) and altered blood pressure in the urban population (ß = 6.66; 95% CI = 2.14;11.18). This occurred both in the raw analysis and in the models adjusted for confounding factors. CONCLUSION: Central adiposity was inversely associated with cortisol in the rural population and directly associated with higher arterial blood pressure in the urban population, suggesting a local influence on how individuals react to stress.


Assuntos
Depressão/epidemiologia , Abastecimento de Alimentos/estatística & dados numéricos , Hipertensão/epidemiologia , Obesidade Abdominal/epidemiologia , Estresse Psicológico/epidemiologia , Adulto , Idoso , Índice de Massa Corporal , Brasil/epidemiologia , Estudos Transversais , Depressão/sangue , Depressão/fisiopatologia , Feminino , Humanos , Hidrocortisona/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Obesidade Abdominal/fisiopatologia , Prevalência , Saúde Pública/estatística & dados numéricos , Fatores de Risco , População Rural , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , População Urbana , Circunferência da Cintura
9.
Nutrition ; 31(1): 90-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25441591

RESUMO

BACKGROUND: Flaxseed is a promising alternative to reduce the risk of diseases associated with body weight excess because it is rich in a-linolenic acid, lignans, and dietary fiber. Flaxseed (Linum usitatissimum) can be found in brown and golden varieties; however, questions have arisen as to whether the variety may influence the health effects. OBJECTIVE: The objective of this study was to compare the effects of brown and golden flaxseeds on lipid profile, glycemia, blood pressure, inflammatory status,body weight, and body composition in overweight adolescents. METHODS: Seventy-five overweight adolescents (33 boys, 42 girls; age 13.7 ! 2.1 y), from Alegre-ES, Brazil, were randomized to one of the three groups (n » 25) on a parallel, single-blind clinical trial. They received 28 g/d of brown flaxseed (BF), golden flaxseed (GF), or the equivalent amount of wheat bran (Control, CG) in different preparations at school from Monday to Friday for 11 wk. Blood pressure, anthropometric evaluation, and the analyses of blood total cholesterol, lipoproteins, glucose, and inflammatory markers were performed at the beginning and at the end of the intervention. The data were analyzed by ANCOVA at 5% significance. RESULTS: The groups who consumed brown and golden flaxseed showed significant reduction in diastolic blood pressure. Brown and golden flaxseed did not differentially affect plasma lipid responses, plasma glucose and inflammatory profile, although all groups (BF, GF, and CG) showed increased levels of TNF-a. CONCLUSIONS: The adolescents consumed about half the daily amount provided, which may not have been sufficient to exert the health benefits of flaxseed reported in the literature, concerning the lipid profile, inflammation biomarkers and body composition.


Assuntos
Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Linho/química , Sobrepeso/dietoterapia , Adiponectina/sangue , Adolescente , Composição Corporal , Índice de Massa Corporal , Peso Corporal , Brasil , Fibras na Dieta/administração & dosagem , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Método Simples-Cego , Fator de Necrose Tumoral alfa/sangue , Circunferência da Cintura , Ácido alfa-Linolênico/análise
10.
Nutr Res ; 28(6): 391-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19083437

RESUMO

The objective of this study was to investigate the effect of iron overload with a hyperlipidemic diet on the histologic feature of hepatic tissue, the lipid and glycemic serum profiles, and the markers of oxidative damage and stress in a rat model. Twenty-four male Fischer rats, purchased from Experimental Nutrition Laboratory, Federal University of Ouro Preto, were assigned to 4 equal groups, 2 were fed a standard cholesterol-free diet (group C or control and CI or control with iron) containing 8.0% soybean oil and 2 were fed a hyperlipidemic diet (group H or hyperlipidemic and HI or hyperlipidemic with iron) containing 1.0% cholesterol and 25.0% soybean oil. A total of 50 mg of iron was administered to rats in groups CI and HI in 5 equal doses (1 every 3 weeks for a 16-week period) by intraperitoneal injections of 0.1 mL of iron dextran solution (100 g Fe(2+)/L; Sigma, St Louis, Mo). The other rats in groups C and H were treated in a similar manner but with sterile saline (0.1 mL). Irrespective of the diet, iron excess enhanced serum triacylglycerols (P < .05) and reduced serum glucose and glycated hemoglobin levels (P < .05) but did not affect serum cholesterol concentration. Histologic analysis showed steatosis in groups H and to a lesser extent in HI. No significant differences (P > .05) were observed in paraoxonase activities or in serum levels of free or total sulfhydryl radicals, malondialdehyde, or total antioxidants. The findings suggest that iron excess in the rat probably modifies lipid metabolism and, as a consequence, alters glucose homeostasis and increases the level of serum triacylglycerols but not of cholesterol.


Assuntos
Glicemia/metabolismo , Fígado Gorduroso/etiologia , Hiperlipidemias/complicações , Sobrecarga de Ferro/complicações , Metabolismo dos Lipídeos/efeitos dos fármacos , Triglicerídeos/sangue , Animais , Antioxidantes/análise , Glicemia/análise , Colesterol/análise , Colesterol/sangue , Colesterol/farmacologia , Gorduras na Dieta/farmacologia , Hemoglobinas Glicadas/análise , Homeostase/efeitos dos fármacos , Ferro/metabolismo , Sobrecarga de Ferro/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/análise , Lipídeos/sangue , Fígado/química , Fígado/enzimologia , Masculino , Ratos , Ratos Endogâmicos F344 , Transferrina/metabolismo
11.
J Nutr ; 133(1): 15-20, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12514260

RESUMO

Epidemiologic and experimental data suggest that excess iron may contribute to the development of cardiovascular diseases (CVD). Because increased LDL cholesterol, decreased HDL cholesterol and alteration of systolic blood pressure (SBP) have all been implicated as risk factors for atherosclerosis and related CVD, the present study was designed to determine whether excess iron alters serum lipids and SBP in control and hypercholesterolemic rats. Female Fischer rats were divided into four groups. The control group (C) was fed the control diet, the CI group was fed the control diet and given iron dextran injections, the hypercholesterolemic group (H) was fed a 1 g/100 g cholesterol diet, and the HI group was fed the cholesterol diet and given iron dextran injections. The rats were fed the diets for 8 wk and iron dextran injections were given during wk 6 at doses of 10 mg/d for 5 d. Excess iron reduced (P < 0.01) plasma total cholesterol in rats fed the cholesterol diet (5.31 +/- 0.83 and 3.17 +/- 0.31 mmol/L for H and HI, respectively). Excess iron also resulted in a redistribution of cholesterol among the various lipoprotein fractions, with an increase (P < 0.01) in HDL cholesterol (0.56 +/- 0.12 and 0.85 +/- 0.16 mmol/L for H and HI, respectively) and a decrease (P < 0.01) in LDL cholesterol (4.49 +/- 0.77 and 2.09 +/- 0.26 mmol/L for H and HI, respectively). This redistribution also occurred in the rats fed the control diet. The treatments did not affect SBP or heart rate. The high cholesterol diet affected iron homeostasis; group H had lower transferrin saturation than group C (P < 0.01); group HI had a lower serum iron concentration than group CI but did not differ from group H (P < 0.05). Therefore, we conclude that if iron has any effect on CVD, it is not through its influence on serum lipids and blood pressure.


Assuntos
Colesterol/sangue , Hipercolesterolemia/metabolismo , Sobrecarga de Ferro/metabolismo , Ferro/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/farmacologia , Feminino , Homeostase/efeitos dos fármacos , Ferro/administração & dosagem , Ferro/sangue , Sobrecarga de Ferro/sangue , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Ratos , Ratos Endogâmicos F344
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