Antichagásicos potenciais: síntese de pró-fármacos recíprocos de megazol e primaquina

A doença de Chagas é uma das doenças parasitárias mais graves da América Latina, apresentando alto impacto sócio-econômico. Nos 21 países endémicos, estima-se que de 16 a 18 milhões de pessoas estejam infectadas pelo parasita e que ocorram, aproximadamente, 50.000 mortes a cada ano. Existem apenas dois fármacos disponíveis para o tratamento, no entanto, tais compostos apresentam alta incidência de efeitos adversos e eficácia inadequada contra a fase crônica da doença. Assim sendo, toma-se de extrema importância a pesquisa por novos compostos tripanomicidas. A alta atividade antichagásica potencial do megazol, derivado nitro-heterocíclico, já foi demonstrada. A primaquina, clinicamente utilizada em malária, também apresenta atividade tripanomicida. A latenciação de fármacos é um dos métodos de modificação molecular que tem como objetivo melhorar as características do fármaco protótipo. Diante do exposto, e devido ao ligeiro sinergismo entre primaquina e megazol, observado em ensaios in vitro com T. cruzi, o objetivo final desse trabalho foi sintetizar pró-fármaco reciproco de megazol e primaquina. Com base na especificidade da cruzipaína, protease encontrada somente no T. cruzi, planejou-se utilizar peptídio - Lys-Arg - e aminoácidos - Lys, Arg - como grupos espaçantes. Inicialmente, pró-fármaco com espaçante succínico inespecífico foi obtido para fins de comparação. No caso dos pró-fármacos recíprocos com espaçantes especificas, chegou-se à síntese dos intermediários: succinilmegazol, éster metílico do succinilmegazol, succinilprimaquina, otimizando-se a síntese de Lys(Cl-Z)-primaquina, Arg(Tos)-primaquina e Lys(Cl-Z)-Arg(Tos)-primaquina. Estes serão, posteriormente, transformados nos derivados de liberação específica potencial. O pró-fármaco com espaçante peptídico provavelmente terá melhor atividade e maior seletividade visto que o composto megazol-succinil-primaquina apresentou elevado valor de IC50, em ensaios in vitro, provavelmente por não estar ocorrendo a liberação completa dos fármacos.Chagas\'s disease is one of the most severe parasitoses of Latin America. According to WHO, over 16 million people are infected and about 50.000 deaths occur in endemic countries annually. Only two drugs are available: benznidazol and nifurtimox. Both are active only in the acute phase of the disease. So, the Jack of effective drugs against the disease leads to an urgent search for new antichagasic agents. Megazol is a nitro-heterocyclic compound with high potential antichagasic activity. Primaquine, clinically used in malaria, also showed tripanomicidal activity. Prodrug design is a molecular modification approach that aims to improve drug properties. Based on those facts, and due to the low sinergism between primaquine and megazol found in in vitro assays with T. cruzi, the final purpose of this work was to synthesize mutual prodrugs of those drugs. Based on the knowledge of cruzipain specificity, protease found only in T. cruzi, peptide - Lys-Arg -- and aminoacids - Lys, Arg -- were planned to be used as spacer groups. Initially, these two drugs were linked through a succinic unspecific spacer group for comparison. ln the case of specific mutual prodrugs, only the synthetic intermediates - succinylmegazol, succinylmegazol methyl ester, succinilprimaquine, Lys(Cl-Z)-primaquine, Arg(Tos)-primaquine and Lys(Cl-Z)-Arg(Tos)-primaquine, which synthesis was optimized - were obtained. These intermediates will be further transformed in specific drug delivery system. Probably, the prodrug with peptide spacer group will have better activity and higher selectivity than the succinic derivative, as expected. The biological assay carried out with megazol-succinyl-primaquine mutual prodrug showed a high value of IC50, probably due to incomplete drug release

Perfil comparativo do custo do tratamento entre pró- fármacos e os seus fármacos precursores

A latenciação é uma importante ferramenta no processo de desenvolvimento de fármacos, pois através dela, diversas barreiras biológicas que limitam o uso de um agente terapêutico podem ser superadas. Assim, esta estratégia permite a reintrodução de substâncias anteriormente descartadas por suas propriedades indesejáveis e o aprimoramento de novos fármacos, antes mesmo que sejam lançados na terapêutica. Embora a latenciação apresente vantagens clínicas, não existem estudos demonstrando a vantagem econômica do uso de pró-fármacos em relação às substâncias precursoras. Dessa forma, o objetivo do presente trabalho foi elaborar um perfil comparativo do custo do tratamento entre pró-fármacos e seus respectivos fármacos precursores, disponíveis no mercado farmacêutico brasileiro, visando demonstrar a real importância da latenciação como ferramenta norteadora para o desenvolvimento de fármacos e, principalmente, a viabilidade financeira do uso de pró-fármacos. Constatou-se que seis do total de pró- fármacos analisados apresentaram-se financeiramente mais vantajosos que os seus precursores e, mesmo para os pró-fármacos que tiveram custo mais elevado, a vantagem clínica alcançada justifica sua utilização

INTERAÇÕES FÁRMACO-RECEPTOR: APLICAÇÕES DE TÉCNICAS COMPUTACIONAIS EM AULA PRÁTICA SOBRE A EVOLUÇÃO DOS INIBIDORES DA ENZIMA CONVERSORA DE ANGIOTENSINA

Teaching classes and events regarding the molecular aspects of drug-receptor interactions is not an easy task. The ligand stereochemistry and the spatial arrangement of the macromolecular targets highly increase the complexity of the process. In this context, the use of alternative and more playful approaches could allow students to gain a more thorough understanding of this important topic in medicinal chemistry. Herein, we describe a practical teaching approach that uses computational strategies as a tool for drug-receptor interaction studies performed for angiotencsin converting enzyme inhibitors (ACEi). Firstly, the students learn how to find the crystallographic structure (enzyme-ligand complex). Then, they proceed to the treatment of crude crystallographic data. Thereafter, they learn how to analyze the positioning of the drug on the active site of the enzyme, looking for regions related to the molecular recognition. At the end of the study, students can summarize the molecular requirements for the interaction and the structure-activity relationships of the studied drugs

UNDERSTANDING THE CHEMICAL PROCESS RELATED TO THE BIOACTIVATION OF SIMVASTATIN THROUGH EXPERIMENTAL AND IN SILICO

Cholesterol is a lipid which in high concentration can be an important risk factor for coronary diseases and atherosclerotic lesions. This lipid presents an endogenous biosynthesis that involves several steps; one of them is modulated by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). HMG-CoA reductase is inhibited by statins, such as simvastatin, in order to reduce seric become active. The structure of simvastatin has a lactone ring that undergoes enzymatic hydrolysis giving the 3,5-dihydroxy-heptanoate metabolite. This group is essential for simvastatin antilipemic activity, but significantly increases their water solubility. Make students understand the influence of chemical groups and organic functions on physicochemical properties and pharmacokinetic profiles of drugs, as simvastatin, is not an easy task. In this context, combine practical strategies and theoretical presentations of the concepts involved on drug biotransformation certainly could improve the teaching learning process. This manuscript correlates organic strategies and in silico techniques throught simvastatin hydrolysis followed by comparative ClogP measurement. This approach intends to allow students to have contact with a cross-platform and multidisciplinary learning, making it ludic, easier and more interesting than theoretical classes

Dillapiole as Antileishmanial Agent: Discovery, Cytotoxic Activity and Preliminary SAR Studies of Dillapiole Analogues

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structureactivity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC50?=?69.3 mu M) and Leishmania brasiliensis (IC50?=?59.4 mu M) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC50?=?99.9 mu M for L. amazonensis and IC50?=?90.5 mu M for L. braziliensis) and 3 (IC50?=?122.9 mu M for L. amazonensis and IC50?=?109.8 mu M for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.MackpesquisaMackpesquis

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived from are also discussed. Considering the importance of these therapeutic classes, from both therapy and economic standpoints, prodrug design is a very valuable aspect in the research of new drugs and for the pharmaceutical industry as a whole.<br>O objetivo do trabalho foi ressaltar a importância do planejamento de pró-fármacos para a terapia, por meio de exemplos disponíveis no mercado farmacêutico brasileiro. Os princípios da latenciação são sucintamente discutidos. Apresentam-se exemplos de pró-fármacos de muitas classes terapêuticas importantes e as vantagens relativas aos fármacos dos quais derivam são, também, discutidas. Considerando-se a importância dessas classes terapêuticas, tanto do aspecto terapêutico quanto do econômico, o planejamento de pró-fármacos representa aspecto de grande valor na busca de novos fármacos e na indústria farmacêutica como um todo