RESUMO
Triketones are suitable compounds for 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition and are important compounds for eliminating agricultural weeds. We report herein quantitative structure-activity relationship (QSAR) modelling and docking studies for a series of triketone-quinoline hybrids and 2-(aryloxyacetyl)cyclohexane-1,3-diones with the aim of proposing new chemical candidates that exhibit improved performance as herbicides. The QSAR models obtained were reliable and predictive (average r2, q2, and r2pred of 0.72, 0.51, and 0.71, respectively). Guided by multivariate image analysis of the PLS regression coefficients and variable importance in projection scores, the substituent effects could be analysed, and a promising derivative with R1 = H, R2 = CN, and R3 = 5,7,8-triCl at the triketone-quinoline scaffold (P18) was proposed. Docking studies demonstrated that π-π stacking interactions and specific interactions between the substituents and amino acid residues in the binding site of the Arabidopsis thaliana HPPD (AtHPPD) enzyme support the desired bioactivity. In addition, compared to a benchmark commercial triketone (mesotrione), the proposed compounds are more lipophilic and less mobile in soil rich in organic matter and are less prone to contaminate groundwater.
Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Arabidopsis , Herbicidas , Quinolinas , Relação Quantitativa Estrutura-Atividade , Modelos Moleculares , Herbicidas/farmacologia , Herbicidas/química , Plantas Daninhas/metabolismo , Arabidopsis/química , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Inibidores Enzimáticos/químicaRESUMO
Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Flaviviridae/enzimologia , Peptídeos/química , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Proteínas Virais/química , Animais , Infecções por Flaviviridae/tratamento farmacológico , Humanos , Estrutura Molecular , Proteínas Virais/antagonistas & inibidoresRESUMO
Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.
Assuntos
Aminoácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores Enzimáticos/farmacologia , Manitol/química , Serina Endopeptidases/química , Carbono/química , Vírus da Dengue/metabolismo , Flavivirus/metabolismo , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Manose/química , Modelos Químicos , Modelos Moleculares , Peptídeos/química , Conformação Proteica , Temperatura , Proteínas não Estruturais Virais/químicaRESUMO
OBJECTIVE: To evaluate glycemic control in type 1 diabetes mellitus patients followed in 1998. PATIENTS AND METHODS: We studied 38 patients [22 males; age = 10.4 -/+ 4.1 years; 12 (31.6%) prepubertal, 26 (68.4%) pubertal], with diabetes duration of 3.7-/+3.4 years and age of diagnosis of 7.2 -/+ 4.7 years. HbA1c was determined using high-performance liquid chromatography (L-9100 Merck Hitachi, reference value =2.6 to 6.2%). RESULTS: HbA1c was 8.04 -/+ 2.4%, without association with gender and puberty. In the 27 patients with at least two HbA1c determinations, the level of glycemic control changed in 8 (29.6%) and remained the same in 19 (70.4%). From these, glycemic control was poor in 3 (11.1%) and good in 16 (59.3%). Among the patients with good glycemic control, HbA1c was always within reference values in 4 (25%); 7 (43.75%) had at least one HbA1c measurement within these limits; and in 5 (31.25%), all HbA1c measurements were above the upper limit of the reference range. There was no association between the last glycemic control evaluation and the number of HbA1c determinations. The intraindividual coefficient of variation of HbA1c in the group that had at least three HbA1c determinations (n = 19) was 11.2 -/+ 5.6% (P = 0.0000). CONCLUSION: In our study, although most patients presented satisfactory glycemic control during the follow-up period, only 4 patients (14.8%) maintained normal values of HbA1c. The variability of HbA1c must be evaluated when considering the interrelation between glycemic control and evolution to microvascular complications in diabetis.
RESUMO
Objetivo. Analisar o perfil de processos infecciosos em diabéticos internados em um hospital geral. Material e Métodos. Foram selecionados, retrospectivamente, 233 prontuários de diabéticos no período de setembro a novembro de 1990. Num total de 38 (16,3 por cento) pacientes com infecçäo, 76,3 por cento (n=29) eram do sexo feminino, com média de idade de 58,9 + 15,3 anos, duraçäo do diabetes de 10,8 + 9,1 anos e predomínio do diabetes melito tipo II na amostra (86,3 por cento, n = 33). Resultados. O principal motivo de internaçäo foi a doença macrovascular de extremidades (42 por cento). Quarenta processos infecciosos foram estudados (dois pacientes apresentavam infecçäo em dois sítios). Foram realizadas culturas em 77,5 por cento dos casos, näo tendo sido observado predomínio de nenhum germe, mesmo nos diferentes sítios. A infecçäo urinária foi a mais freqüente (55 por cento, n = 22, p < 0,01) e, dessa amostra, 86,4 por cento (n = 19) eram do sexo feminino. A sepse ocorreu em 18,4 por cento (n = 7) dos pacientes; destes, a infecçäo pulmonar foi responsável por 71,4 por cento. Todos os casos de sepse foram a óbito. Conclusäo. CCnsiderando as infecçöes um fator agravante no processo mórbido de diabéticos, torna-se importante a realizaçäo de medidas profiláticas a fim de evitar o seu surgimento.
Assuntos
Adulto , Pessoa de Meia-Idade , Feminino , Humanos , Infecção Hospitalar/complicações , Diabetes Mellitus/complicações , Idoso de 80 Anos ou mais , Infecção Hospitalar/diagnóstico , Estudos RetrospectivosRESUMO
BACKGROUND: To analyse the infectious diseases of inpatient diabetics in a general hospital. MATERIAL AND METHODS: We selected retrospectively 233 records of diabetics admitted during September, October and November 1990. There were 38 (16.3%) patients with infection, age 58.9 +/- 15.3 years, 29 (76.3%) were female, duration of diabetes were 10.8 +/- 9.1 years and 86.3% (n = 33) were possibly DM type II. RESULTS: Peripheral macrovascular disease was the main cause of admission (42%). Forty infectious processes were analysed (two patients had two sites of infection). Cultures were performed in 77.5% of the cases and no microorganism predominated, even when different sites of infection were analysed. Urinary tract infection were the most frequent one (55%, n = 22), and 86.4% (n = 19) of them were observed in female. Pulmonary infections accounted for 71.4% of the cases of sepsis which occurred in 18.4% (n = 7) of our population. All patients with sepsis died. CONCLUSION: Considering infections a worsening factor for diabetic patients we could conclude that it is important to perform some prophylatic measures to avoid them.