Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of β-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate π-facial selectivity critically dependent upon the nature of the β-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the β-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.
The asymmetric total synthesis of pironetin, a compound that shows plant growth regulatory activity, immunosuppressive as well as a remarkable antitumoral activity, is described. The approach involves the use of three very efficient Evans oxazolidinone-mediated syn-aldol condensations, a high-yielding coupling between lithium acetylide ethylenediamine complex and a tosylate followed by methylation, and selective reduction to establish the C12−C13 (E) double bond.
Resumo: A Campanha da Fraternidade de 2014 abordara o trafico humano, um crime contra a humanidade que desafia a civilizacao atual no inicio do seculo XXI. O presente artigo procura explicitar a perspectiva da CF perante esta grave situacao. Tendo como referencia o texto-base, serao apresentadas algumas motivacoes: a nocao de trafico humano e suas principais modalidades; a gravidade desta situacao que atenta contra a dignidade humana e os direitos fundamentais dos filhos e filhas de Deus, bem como alguns elementos biblicoteologicos. Por fim, a proposta de enfrentamento desta cruel realidade que exige a convergencia de forcas de diferentes atores. Abstract: A Campanha da Fraternidade de 2014 deals with an excruciating problem of the marketing of human beings, reducing a person to mere commodities for lucrative aims. Since the past until this century trading human beings in flesh and blood as well as single pieces of dismembered bodies are for sale to be purchased by interested costumers among almost all continents. The basic of the campaign within the Church in Brazil is being analyzed in an all embracing functional perspective regarding the main and focused most of all on the aggression of human dignity and the fundamental human rights, with special emphasis on the personal excellence as children of God in the light of selected texts from the Bible. The last chapter provides detailed suggestions for further clarifications and practical operations.
No CAPITULO I discutimos os fatores experimentais que controlam a diatereosseletividade 1,3 na reducao de b-aminocetonas aciclicas (+/-)-1. Na reducao com Zn(BH4)2, em eter/THF a 0°C, os g-aminoalcoois (+/- )-2(SYN) foram obtidos em bons excessos diastereoisomericos, quando R= -t-C4H9, -C6H5, -i-C4H9 e -i-C3H7 e os grupos -R, -R e -R sao aromaticos ou aromaticos substituidos. Nas reducoes com LiEt3BH, em THF a -78°C, os g-aminoalcoois (+/-)-3(ANTI) foram obtidos em bons excessos diastereoisomericos apenas quando os substituintes no nitrogenio e no carbono b sao grupos arila ou arila substituidos. Em uma aplicacao sintetica do estudo anterior (CAPITULO II), o alcaloide piperidinico (+/-)-Sedamina 18 foi preparado em 6 etapas, a partir da d-valerolactama 101, em 69% de rendimento total (85% de excesso diastereoisomerico). A rota empregada envolveu a adicao de 1-trimetil-sililoxi-1-fenil-eteno a N-terc-butoxi-carbonil-2-etoxi-piperidina (+/-)-103a, catalisada por trifluorometanossulfonato de trimetilsilila (TMSOTf) ou triflato de di-n-butil boro (n-Bu2BOTf), levando a formacao do cetocarbamato (+/-)-107a. Reducao da 2-fenacilpiperidina (+/-)-14 (obtida por desprotecao do cetocarbamato (+/-)-107a) com Zn(BH4)2 em eter/THF, a -78°C, conduziu ao g-aminoalcool (+/-)-nor-Sedamina 15. Metilacao redutiva da (+/-)-nor-Sedamina (formaldeido/NaBH3CN) forneceu o alcaloide (+/-)-Sedamina 18. No CAPITULO III, o alcaloide quinolizidinico (+/-)-Mirtina 121 foi preparado em tres etapas a partir da d-valerolactama 101, em 59% de rendimento total. A mistura bruta, obtida apos a reacao de condensacao entre o sililenoleter 136 e o ion N-aciliminio 98, foi mantida sob agitacao com solucao saturada de NaHCO3 por 24 horas, conduzindo a formacao majoritaria do alcaloide quinolizidinico (+/-)-Mirtina 121 (produto majoritario de uma reacao controlada cineticamente), em um unico frasco reacional, via reacao de Michael intramolecular do intermediario (+/-)-134. O alcaloide quinolizidinico (+/-)-Lasubina II 140 foi preparado em 5 etapas a partir da d-valerolactama 101, em 55% de rendimento total. A etapa chave nesta sintese foi a reacao de condensacao entre o sililenoleter 161 e o ion N-aciliminio 98, formado atraves da adicao de TMSOTf ao a-etoxicarbamato (+/-)-103a. Esta condensacao forneceu, em um unico frasco reacional, apos desprotecao do nitrogenio e reacao de Michael intramolecular, uma mistura das quinolizidin-2-onas (+/-)-142 e (+/-)-141 na proporcao de 3:2, respectivamente, que pode ser isomerizada para o isomero (+/-)-141, termodinamicamente mais estavel. Reducao da quinolizidin-2-ona (+/-)-141 com LS-Selectride forneceu (+/-)-Lasubina lI, em 96% de excesso diastereoisomerico. No CAPITULO IV, o alcaloide (3R,5R,9R)-(-)-Indolizidina 223AB 166 foi sintetizado em 8 etapas e 8% de rendimento total a partir do acido S-(-)-Piroglutâmico 182. Esta sintese baseia-se na reacao de condensacao entre o sililenoleter 190 e o ion N-aciliminio 189, fornecendo as indolizidonas (-)-204 e (-)-205, na proporcao de 1,5: 1, respectivamente. Apos purifificacao por coluna cromatografica, a tosil-hidrazona correspondente a indolizidinona (-)-204 foi reduzida com NaBH4 em EtOH, sob refluxo, fornecendo o alcaloide (3R,5S,9R)-(-)-Indolizidina 171 em 22% de rendimento total. Analogamente, (-)-205 foi transformado no alcaloide (3R,5R,9R)-(-)-Indolizidina 223AB 166, espectroscopicamente identico (H e C-RMN) ao produto natural. Esta sequencia de reacoes: adicao a ion N-aciliminio / descarboxilacao / adicao de Michael e uma rota bastante pratica e eficiente para a obtencao de sistemas quinolizidinicos e indolizidinicos, sendo potencialmente util para aplicacao na sintese de outros alcaloides biologicamente ativos.
Abstract
the authors highlighted the important aspects of science and technology with special emphasis on the field of Chemistry and its contributions toward a more prosperous Brazil of future.As a second step in that direction, this article extends the discussion of a key issue for the country in the framework of the chemistry community through the so called position papers in strategic areas.This document is a part of the contribution of the Brazilian Chemical Society to the World Science Forum to be held in Rio de Janeiro in November 2013.In this context, the present paper provides a brief discussion on neglected tropical diseases (NTDs) with emphasis on the current challenges and opportunities towards the development and evolution of the field.NTDs leads to illness, long-term disability or death, and has severe social, economic and psychological consequences for millions of men, women, and children worldwide.In most cases, the available treatments are inadequate and extremely limited in terms of efficacy and safety, leading to an urgent demand for new drugs.In addition to the traditional challenges involved in any drug discovery process, it is widely recognized that there is an innovation gap and a lack of investment for research and development (R&D) in the area of NTDs.In the last few decades, methods toward combating, eradication, prevention, and treatment of NTDs have been repeatedly emphasized in the major international agendas.Developments in these strategies and alliances have continued to have an essential impact, particularly in the area of drug discovery, both in Brazil and globally and should be encouraged and supported.Several examples of international activities dedicated to the reduction of the devastating global impact of NTDs can be provided.Despite the beneficial developments in the past 30 years, NTDs continue to devastate poor communities in remote and vulnerable areas, in large part, due to market failures and public policies.Recent studies have shown that among 756 new drugs approved between 2000 and 2011, only four new chemical entities (NCEs) were identified for the treatment of malaria, while none were developed against NTDs or tuberculosis.Furthermore, only 1.4% of approximately 150,000 clinical trials were registered for neglected diseases, with a smaller number of trials for NCEs.Establishment and strengthening of global strategies involving the triad "government-academia-industry" is fundamental to the success in R&D of new drugs for NTDs.National and international public-private initiatives that aim to create, encourage, and invest in R&D projects have been implemented and therefore are of utmost importance to successfully integrate Brazil into this new paradigm.It is essential to lay the foundation for mechanisms that will intensify investments in infrastructure, training, and qualification of personnel with an ultimate strategic vision that foresees continuity.Our research group has made significant contributions to the development of this field with the goal of forging new frontiers while tackling both current and future challenges that include indispensable elements such as innovation and integration.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Elaiophylin (1), a glycosidic polyketide, was first isolated from the cultures of Streptomyces melanosporus by Arcamone et al.1a and by Arai1b from a related microorganism. Elaiophylin is a 16- membered macrolide which displays a wide range of bioactivities such as antimicrobial, cell cycle inhibition, apoptosis induction, immunosuppressive, anthelmintic, inhibition of K+-dependent adenosine triphosphatases, and plant growth inhibition. Due to the pronounced activity showed by this macrolide, we are interested in to investigate its biosynthesis by analyzing the interaction between the elaiophylin enzyme thioesterase and the fragments 2-5.
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