RESUMO
The emergence of the COVID-19 has caused public health problems worldwide and there is no effective pharmacological treatment for this disease. Research on 3D models of proteins and the search for active molecular sites are important tools to assist in the discovery of effective antiviral drugs to combat COVID-19. To address this problem, the 3D protein structures of SARS-CoV 2 were analyzed and submitted to cavities research, evaluation of their druggabillity and liganbility, and applied to molecular docking studies with potential ligand candidates actually assayed against COVID-19. Eight druggable potential cavity sites were determined in model structures' PDB code, 6W4B, 6VWW, 6W01, 6M3M, and 6VYO, and these are the good alternatives to be characterized as targets for antiviral compounds. The good cavity model of the protease 3D structure was used in molecular docking, and this allowed verifying the theoric interactions of this protein and lopinavir and ritonavir antiviral drugs. These results may assist in the use of 3D protein models in drug design studies aiming to develop drugs against the COVID-19 pandemic.
Assuntos
COVID-19/virologia , Simulação de Acoplamento Molecular , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Domínio Catalítico , Simulação por Computador , Proteínas do Nucleocapsídeo de Coronavírus/química , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Fosfoproteínas/química , Ligação Proteica , Conformação Proteica , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Proteínas da Matriz Viral/química , Tratamento Farmacológico da COVID-19RESUMO
A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78⯵M, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Ovarianas/tratamento farmacológico , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Ovarianas/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.
Assuntos
Anti-Inflamatórios/síntese química , Piridonas/química , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Peroxidase/metabolismo , Piridonas/metabolismo , Piridonas/uso terapêutico , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The γ-hexalactone is a flavoring agent for alcoholic beverages, teas, breads, dairy products, coffees, buttery products among others. It presents low molecular weight and exhibits sweet fruity aroma with nuances of nuts. As far as we know, both literature and government regulations have gaps regarding the safe use of the γ-hexalactone. In this context, the main objective of this work was to evaluate the effects of γ-hexalactone through in silico and in vitro approaches. METHODS: The in silico analysis was performed through four free online platforms (admetSAR, Osiris Property Explorer®, pkCSM platform and PreADMET) and consisted of comparative structural analysis with substances present in databases. The computational prediction was performed in the sense of complement and guide the in vitro tests. Regarding in vitro investigations, screening of cytotoxicity (assessed by cell proliferation and viability parameters) in lymphocytes exposed to γ-hexalactone for 72 h were carried out previously to determine non-cytotoxic concentrations. Following this screening, concentrations of 5.15, 0.515, and 0.0515 µM were selected for the study of the respective potentials: genotoxic (assessed by DNA comet assay), chromosomal mutation (analysis of micronucleus frequency) and immunomodulatory (cytokine quantification using ELISA immunoassay). The results of in vitro assays were compared by one-way analysis of variance (ANOVA), followed by Bonferroni's post hoc test, conducted by statistic software. RESULTS: The platform PreADMET pointed out that γ-hexalactone is potentially mutagenic and carcinogenic. The comet assay data corroborate with these results demonstrating that γ-hexalactone at 5.15 µM caused lymphocytes DNA damage. In relation to cytokine secretion, the results indicate that lymphocytes were activated by γ-hexalactone at non-cytotoxic concentrations, involving an increase in the IL-1 levels in all tested concentrations, ranging from approximately 56 to 93%. The γ-hexalactone only at 5.15 µM induced increase in the levels of IL-6 (~ 60%), TNF-α (~ 68%) and IFN-γ (~ 29%), but decreased IL-10 (~ 46%) in comparison with the negative control (p < 0.05). No change was observed in total lymphocytes or in cell viability at the concentrations tested. CONCLUSIONS: In summary, the γ-hexalactone demonstrated immunomodulatory and genotoxic effects at non-cytotoxic concentrations in healthy lymphocytes.
Assuntos
Citocinas/metabolismo , Dano ao DNA , Aromatizantes/toxicidade , Lactonas/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Mutagênicos/toxicidade , Adulto , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Adulto JovemRESUMO
Crossbreeding represents an important technique to improve growth, beef quality and adaptability in beef production systems in tropical countries. The aim of this study was to evaluate sire and dam breed effects on performance and carcass traits of crossbred cattle produced in a tropical environment. Heifers and steers were evaluated during the pre-weaning, the post-weaning (n = 173) and the finishing phase (n = 123). Animals were produced by mating Nellore (N_N), Angus × Nellore (A_N) and Caracu × Nellore (C_N) dams with Braford, Charbray and Caracu sires. After weaning, animals were raised grazing on Marandu grass for 12 months; thereafter they were housed in individual pens and finished in a feedlot, receiving a total mixed ration. Ultrasound carcass evaluations were performed to determine ribeye area (R_A), backfat thickness (B_T) and rump fat thickness (R_T). A_N progeny were heavier at birth than N_N (P < 0.05), and Braford progeny had greater birth BW than Caracu (P < 0.05). Greater weaning BW was observed in the A_N and C_N offspring compared to N_N (P < 0.01). Greater average daily gain during the post-weaning period was verified in the N_N progeny compared to C_N (P < 0.05). No dam or sire breed effects were observed for BW at the end of the post-weaning period (P > 0.05). Progeny of N_N cows had greater B_T (P < 0.05) and R_T (P < 0.01) at the end of the post-weaning period in relation to C_N. Greater R_A was observed in the Caracu progeny than in the Braford (P < 0.05), which showed greater R_T than the Charbray progeny at the end of the post-weaning period (P < 0.05). No dam or sire breed effects were verified for final BW at the feedlot or for feed efficiency traits (P > 0.05). A_N progeny were superior in final B_T compared to C_N (P < 0.01), and Braford progeny had greater R_T at the end of finishing than Charbray (P = 0.05). The use of crossbred dams allows an increase in productivity until weaning, but this is not maintained in the post-weaning and finishing periods. The use of Braford sires produces similar growth performance in the different stages of the production system to those seen with Charbray and Caracu sires but generates animals with higher fat thickness at the end of finishing, which may improve carcass quality and commercial value.
Assuntos
Bovinos/fisiologia , Hibridização Genética , Carne Vermelha/normas , Animais , Composição Corporal , Cruzamento , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Feminino , Masculino , Parto , Fenótipo , Gravidez , Ultrassonografia/veterinária , DesmameRESUMO
Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100⯵M (GI50 88.4-12.2⯵M). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI50 12.2⯵M), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2⯵M). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Lignanas/química , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , NADH NADPH Oxirredutases/antagonistas & inibidores , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Células THP-1 , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
The present study aimed to evaluate the feedlot performance, profitability and carcass traits of Brahman bulls classified according to the residual feed intake (RFI). Twenty-four bulls (19-month old, 370±34kg live weight) were housed in individual pens for 54 days and had the daily feed intake (observed dry matter intake, DMIobs; DMI % live weight, LW) and average daily gain (ADG) measured. Ultrasound carcass evaluations were performed at the initial and final weighings, when measurements were taken of Longissimus dorsi area, ratio, Longissimus and Biceps femoris fat thickness. The animals were ranked and divided into high (>+0.5 standard deviation; SD), medium (between ±0.5 SD from the mean), and low (<-0.5 SD) RFI groups. Low-RFI animals had lower DMIobs (P<0.10) and DMI % LW (P<0.05). No significant differences in initial and final weight or ADG were noticed (P>0.05). Low-RFI animals showed lower weight gain cost and higher daily profit (P<0.05). Carcass traits were similar between groups, regardless of evaluation date (P>0.05). Selection for RFI lead to animals with lower feed intake without affecting weight gain or carcass traits, thereby providing increased profitability for beef cattle farming.(AU)
Objetivou-se avaliar o desempenho, o lucro e as características de carcaça de tourinhos Brahman classificados de acordo com o consumo alimentar residual (CAR). Vinte e quatro tourinhos (19 meses de idade e 370±34kg de peso vivo) foram alojados em baias individuais por 54 dias para avaliação do consumo de alimentos (CMSobs; CMS % peso vivo, PV) e ganho de peso diário (GMD). Avaliações de carcaça por ultrassonografia foram realizadas nas pesagens inicial e final, com mensurações da área do Longissimus dorsi, ratio, espessura de gordura sobre o Longissimus e sobre o Biceps femoris. Os animais foram ranqueados e divididos em grupos de alto (>+0,5 desvio-padrão; DP), médio (entre ±0,5 DP da média) e baixo (<-0,5 DP) CAR. Animais de baixo CAR apresentaram menor CMSobs (P<0,10) e menor CMS % PV (P<0,05). Não houve diferença nos pesos inicial e final e GMD (P>0,05). Animais de baixo CAR apresentaram menor custo do ganho de peso e maior lucro diário (P<0,05). As características de carcaça foram semelhantes entre os grupos independentemente da data de avaliação (P>0,05). A seleção para CAR leva a animais de menor consumo, sem afetar o ganho de peso e as características de carcaça, fornecendo maior lucro para a atividade pecuária.(AU)
Assuntos
Animais , Bovinos , Bovinos/genética , Bovinos/fisiologia , Ingestão de Alimentos , Carne/análiseRESUMO
The present study aimed to evaluate the feedlot performance, profitability and carcass traits of Brahman bulls classified according to the residual feed intake (RFI). Twenty-four bulls (19-month old, 370±34kg live weight) were housed in individual pens for 54 days and had the daily feed intake (observed dry matter intake, DMIobs; DMI % live weight, LW) and average daily gain (ADG) measured. Ultrasound carcass evaluations were performed at the initial and final weighings, when measurements were taken of Longissimus dorsi area, ratio, Longissimus and Biceps femoris fat thickness. The animals were ranked and divided into high (>+0.5 standard deviation; SD), medium (between ±0.5 SD from the mean), and low (<-0.5 SD) RFI groups. Low-RFI animals had lower DMIobs (P<0.10) and DMI % LW (P<0.05). No significant differences in initial and final weight or ADG were noticed (P>0.05). Low-RFI animals showed lower weight gain cost and higher daily profit (P<0.05). Carcass traits were similar between groups, regardless of evaluation date (P>0.05). Selection for RFI lead to animals with lower feed intake without affecting weight gain or carcass traits, thereby providing increased profitability for beef cattle farming.(AU)
Objetivou-se avaliar o desempenho, o lucro e as características de carcaça de tourinhos Brahman classificados de acordo com o consumo alimentar residual (CAR). Vinte e quatro tourinhos (19 meses de idade e 370±34kg de peso vivo) foram alojados em baias individuais por 54 dias para avaliação do consumo de alimentos (CMSobs; CMS % peso vivo, PV) e ganho de peso diário (GMD). Avaliações de carcaça por ultrassonografia foram realizadas nas pesagens inicial e final, com mensurações da área do Longissimus dorsi, ratio, espessura de gordura sobre o Longissimus e sobre o Biceps femoris. Os animais foram ranqueados e divididos em grupos de alto (>+0,5 desvio-padrão; DP), médio (entre ±0,5 DP da média) e baixo (<-0,5 DP) CAR. Animais de baixo CAR apresentaram menor CMSobs (P<0,10) e menor CMS % PV (P<0,05). Não houve diferença nos pesos inicial e final e GMD (P>0,05). Animais de baixo CAR apresentaram menor custo do ganho de peso e maior lucro diário (P<0,05). As características de carcaça foram semelhantes entre os grupos independentemente da data de avaliação (P>0,05). A seleção para CAR leva a animais de menor consumo, sem afetar o ganho de peso e as características de carcaça, fornecendo maior lucro para a atividade pecuária.(AU)
Assuntos
Animais , Bovinos , Carne/análise , Ingestão de Alimentos , Bovinos/fisiologia , Bovinos/genéticaRESUMO
A new series of pyrazolo[3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro antileishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that the pyrazolo[3,4-d]-pyridazin-7-one-N-acylhydrazone-(bi)thiophene hybrids 5b, 6b and 6d exhibit better antileishmanial activity with IC50 84.96, 3.63 and 10.79 µM, against the promastigote form and IC50 32.71, 2.32 and >100 µM against the axenic amastigote form, respectively. The active compounds had their cytotoxicity tested against macrophages and fibroblast cells with a higher selectivity index than 10 for compounds 6b and 6d. Molecular docking studies were performed for all active compounds using the enzyme trypanothione reductase (TR) to investigate a possible action mechanism. The results suggested that active compounds had interactions with the residues of amino acids Gly 13, Thr 51, Thr 160, Gly 161, Tyr 198, Arg 287, Asp 327, Thr 335, which may inhibit the enzyme TR.
Assuntos
Desenho de Fármacos , Leishmania mexicana/efeitos dos fármacos , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Técnicas de Química Sintética , Concentração Inibidora 50 , Leishmania mexicana/enzimologia , Camundongos , Simulação de Acoplamento Molecular , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/metabolismo , Testes de Sensibilidade Parasitária , Conformação Proteica , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/metabolismoRESUMO
In this study, the authors analysed retrospectively 161 patients with acquired immunodeficiency syndrome interned at the Hospital de Clinicas de Porto Alegre. 115 (71.4%) presented with otolaryngologic lesions. 92.2% were male. The great majority were white and aged between 20 and 50 years of age (88.7%). Homosexual and bisexual males were the most frequent risk group (72.2%). Oropharyngeal candidiasis was the most prevalent head and neck manifestation (86%). Other less common lesions were sinusitis (19.1%) and Kaposi sarcoma (7.8%), mainly on the hard palate. The recognition of these manifestations by the otolaryngologist is important in order to make an early diagnosis and to treat them.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Infecções Oportunistas , Otorrinolaringopatias/etiologia , Adolescente , Adulto , Candidíase/etiologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Otorrinolaringopatias/epidemiologia , Otorrinolaringopatias/patologiaAssuntos
Características da Família , Habitação , Transtornos Psicóticos , Adolescente , Adulto , Brasil , Doença Crônica , Feminino , Humanos , Masculino , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
Mediante uma pesquisa de campo, entrevistou-se em suas residencias 50 pessoas portadoras de disturbio psicotico cronico tidas como esquizofrenicas (casos) e 50 pessoas sem historia anterior de disturbio psiquiatrico (controles) juntamente com um informante. Objetivou-se estudar as condicoes de vida do doente psicotico cronico na comunidade atraves de uma abordagem psicossocial. Neste trabalho sao apresentados aspectos referentes as caracteristicas habitacionais e familiares dos dois grupos. Concluiu-se que os casos e controles constituem grupos distintos quanto aos aspectos analisados, ressaltando-se a tendencia a mobilidade descendente apresentada pelos casos, como tambem a existencia de um nucleo familiar pouco estruturado
Assuntos
Adolescente , Adulto , Humanos , Masculino , Feminino , Características da Família , Habitação , Transtornos Psicóticos , BrasilRESUMO
The author describes the methods used in designing a questionnaire for studying curricular priorities in the areas of medical psychology and psychiatry by taking a survey of opinions and suggestions among the medical profession. A private study was done and a draft questionnaire tested with the cooperation of 40 faculty members of two public medical schools in São Paulo state. It is suggested that this methodology could be used for similar purposes in other areas of medical education.