Optimización de derivados benzimidazólicos e imidazólicos contra la enfermedad de Chagas

Descargue el texto completo en el repositorio institucional de la Universidade Estadual de Campinas: https://hdl.handle.net/20.500.12733/3064El proyecto consistió en el diseño, síntesis, optimización y evaluación biológica de compuestos con actividad anti-T. cruzi, parásito causador de la enfermedad de Chagas, utilizando estrategias de química medicinal y síntesis. La exploración desarrollada abarcó dos series de estudio: benzimidazólica e imidazólica, las cuales fueron estudiadas en paralelo, considerando la evaluación de parámetros biológicos in vitro como: actividad anti-tripanocida, citotoxicidad, lipofilicidad (elogD), permeabilidad (PAMPA) y clearance microsomal intrínseco; además de la evaluación de parasitemia en ensayos in vivo para compuestos con mejor perfil biológico preliminar. Los compuestos con mejor perfil biológico considerando una optimización multi-paramétrica presentaron valores de actividad in vitro de IC₅₀ < 10 μM contra el T. cruzi y valores de clearance microsomal intrínseco de CLᵢₙₜ,ᴍ ~ 30 L/h/kg y CLᵢₙₜ,H ~ 1.6 L/h/kg. Los resultados de parasitemia demostraron que para dos compuestos seleccionados correspondientes a la serie imidazólica, se consigue una reducción del 51% y 38% a una dosis de 150mg/kg en ratones femeninos Swiss. A pesar de tratarse de porcentajes menores al obtenido con el fármaco comercial Benznidazol (98%), evidencian la importancia de la serie de estudio para posteriores exploraciones que permitan mejorar el perfil farmacocinético y conseguir una mayor tasa de reducción de parasitemia in vivo.A doença de Chagas é uma doença tropical negligenciada que tem se expandido em diversas partes do globo, tornando-se preocupação mundial por não contar, na atualidade, com a existência de um fármaco que seja eficaz em todas as fases da doença e por afetar, principalmente, populações vulneráveis, com difícil acesso ao diagnóstico e tratamento, condições nas quais a doença pode chegar a ser mortal. Assim, mediante uma abordagem baseada no desenho e otimização de compostos por estratégias da química medicinal, em duas series estudadas em paralelo, imidazol-piperazina e benzimidazólica, buscou-se descobrir novos compostos ativos contra o Trypanosoma cruzi, parasita causador da doença de Chagas, e contribuir à descoberta de novos fármacos para combatê-la. A série imidazólica, desenvolvida como subclasse de uma série explorada previamente pelo grupo de pesquisa, foi estudada com o objetivo de construir a relação estrutura-atividade da série, baseada no perfil biológico contra o T. cruzi, assim como perfilar compostos metabolicamente estáveis mediante uma exploração robusta com diferentes modificações estruturais. A série benzimidazólica, amplamente estudada no grupo de pesquisas com um bom perfil inibitório contra a enzima cruzaína e o T. cruzi, foi estudada com o objetivo de otimizar o perfil metabólico, sem perder atividade biológica, mediante uma abordagem baseada em três considerações: análise da exploração prévia, de pontos susceptíveis ao metabolismo e de inspeção por docagem molecular. Deste modo, foram sintetizados 63 compostos finais correspondentes às duas séries: imidazol-piperazina e benzimidazólica. Os compostos que mais destacaram não apresentaram citotoxicidade em células de mamíferos, obtiveram valores de IC₅₀ < 10 µM contra o T. cruzi e boa estabilidade metabólica, segundo valores de clearance microssomal in vitro (CLintᵢₙₜ,ᵤ,ᴍ ~ 30 L/h/kg e CLᵢₙₜ,ᵤ,H ~ 1,6 L/h/kg), sendo dois compostos selecionados para avaliação de parasitemia. Assim, os derivados selecionados, correspondentes à série imidazol-piperazina, 129 e 130, reduziram a parasitemia em até 51% e 38%, respectivamente, em uma dose de 150mg/kg no pico máximo de infecção, contudo obtiveram uma redução de parasitemia menor do que a obtida pelo fármaco Benznidazol, 98%, revelando que são bons compostos protótipos, mas que precisam ser otimizados estruturalmente para melhorar o perfil farmacocinético, o qual pode ser o responsável pela parasitemia obtida.Brasil. Ministério da Educação. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes

Dereplication Guided Discovery of Secondary Metabolites of Mixed Biosynthetic Origin from<i> Aspergillus aculeatus</i>

Investigation of the chemical profile of the industrially important black filamentous fungus Aspergillus aculeatus by UHPLC-DAD-HRMS and subsequent dereplication has led to the discovery of several novel compounds. Isolation and extensive 1D and 2D NMR spectroscopic analyses allowed for structural elucidation of a dioxomorpholine, a unique okaramine, an aflavinine and three novel structures of mixed biosynthetic origin, which we have named aculenes A–C. Moreover, known analogues of calbistrins, okaramines and secalonic acids were detected. All novel compounds were tested for antifungal activity against Candida albicans, however all showed only weak or no activity. Aspergillus aculeatus IBT 21030 was additionally shown to be capable of producing sclerotia. Examination of the sclerotia revealed a highly regulated production of metabolites in these morphological structures

Experimental investigation of in situ upgrading of heavy oil by using a hydrogen donor and catalyst during steam injection

Experiments were conducted to investigate the feasibility of in situ upgrading of heavy oil by the use of an orgametallic catalyst and a hydrogen donor (tetralin). The experiments used a vertical injection cell into which a mixture of sand, water, and Jobo oil was thoroughly mixed and packed. Two types of runs were conducted: a run where the tetralin and catalyst were mixed within the mixture before packing into the cell, and the other was conducted by injecting a slug of the tetralin-catalyst solution before commencing with the steam injection. The Jobo oil used had an oil gravity of 12.4° API and a viscosity of 7800 cp at 30°C. The injection cell was placed in a vacuum jacket and set to a reservoir temperature of 50°C. Superheated steam at 273°C was then injected into the injection cell at a rate of 5.5 cc/min (cold water equivalent). The cell outlet pressure was maintained at 500 psig. Produced liquid samples were collected periodically through a series of separators. The produced oil was divided into two halves and several measurements and analyses were carried out on them. These included viscosity, density, elemental analysis and liquid composition. Experimental results indicated that tetralin alone was a worthy additive and increased recovery by 15% compared to that of pure steam. The premixed tetralincatalyst run showed improved recovery to that of pure steam by 20%. Experiments also showed that, when the tetralin-catalyst solution was injected rather than mixed, the results were equivalent to tetralin injection runs. Oil production acceleration was displayed by all the runs with tetralin and tetralin-catalyst but was more pronounced with the availability of catalyst

Claude Vandeloise : bibliographie des travaux / bibliography of his works

International audienceThis publication presents an inventory of the research works written by Claude Vandeloise in the course of his career as a linguist. A list of more than 90 references published during the period 1979-2010 is provided, which are divided up into the following headings: books, edited books and journal issues, contributions to journals and books, others, reviews. This compilation adds to a brief biography of Claude Vandeloise published in 2008 in the cognitive science journal "Gogoa" [8 (1)]: "Claude Vandeloise: obra baten mugarriak / Claude Vandeloise: the milestones of his work".Cette publication est le fruit du récolement des travaux de recherche réalisés par Claude Vandeloise (1944-2007) au cours de sa carrière de linguiste. Elle présente une liste de plus de 90 références parues durant la période 1979-2010 et réparties selon les rubriques suivantes : ouvrages, édition d'ouvrages et de numéros de revues, contributions à des revues et à des ouvrages, autres, comptes rendus. Ce recensement vient compléter une brève biographie de Claude Vandeloise parue en 2008 dans la revue de sciences cognitives "Gogoa" [8 (1)]: "Claude Vandeloise: obra baten mugarriak / Claude Vandeloise: the milestones of his work"

The effects of cadmium on plankton populations under different manurial treatments

Recovery of plankton populations from exposure to 1 mg/l of cadmium was studied in an outdoor bioassay using inorganic fertilizers, cow dung or poultry litter as nutrient additions. Although 99% oj the plankton populations were eliminated immediately after exposure to cadmium, both zoo- and phytoplankton densities began reappearing at a slow rate from Day 15 of treatment. Zoo plankton populations of the treated vats became numerically comparable to the control within 55 days of treatment. Poultry litter effected a quicker recovery of zooplankton populations. However, phytoplankton populations did not recover from the cadmium stress in any of the nutrient treatments even after 55 days. Dissolved cadmium was present in solution up to Day 15, while in the other treatments it persisted up to 25 days

Pricing Weather Insurance with a Random Strike Price: An Application to the Ontario Ice Wine Harvest

Interest is growing in weather insurance within the agricultural sector but its use has been limited by the difficulty in defining the appropriate weather event and the lack of agreement on how to price the product. In this paper we develop a new insurance pricing method for weather insurance under situations where volume returns depend not only on the occurrence of the weather event, but also its timing. The method is applied to the pricing of weather insurance for ice wine in the Niagara Peninsula of southern Ontario. Because the harvest quantity of grapes for ice wine degrades over time, the strike value on the weather event measured as harvestable hours is random. This random strike, we developed a systematic approach to valuing the insurance using first, the single index model to capture inter-temporal covariance effects, and then a Monte Carlo simulation protocol to estimate the premium. While this study investigated a model unique to ice wine production in particular, the ideas can be extended to a number of other agricultural situations in which weather affects critical timing in the production process.Risk and Uncertainty,