anb3 exerce papel importante. Os antagonistas da integrina 3 têm efeitos diretos na prevenção do crescimento, angiogênese e metástase tumorais. A avaliação in vitro frente à integrina 3 de coleções de ciclopeptídeos levou a compostos muito ativos e seletivos. Antagonistas não-peptídicos da integrina 3 também foram planejados e sintetizados. A partir da determinação da estrutura tridimensional da integrina 3 complexada com um inibidor, tornou-se possível o planejamento racional de ligantes com alta afinidade. Além disto, estes estudos permitiram a validação e o refinamento de modelo farmacofórico para os inibidores da integrina 3.]]>
. Quinine and quinidine are well-known 4-quinolinecarbinolamines that exhibit antimalarial activity, but, in contrast, their epimers 9-epiquinine and 9-epiquinidine are almost inactive. Literature data are conflicting in describing the 4-quinolinecarbinolamine interaction mode with the molecular target, the ferriprotoporphyrin IX [Fe(III)PPIX]. In the present paper, a pharmacophore is proposed based on the binding of the nonaromatic nitrogen to the iron atom. The 4-quinolinecarbinolamine antimalarials were superimposed on the pharmacophore under consideration and complexes with Fe(III)PPIX were constructed. Conformational analyses of the complexes were performed applying the MM+ molecular mechanics method. The analysis of the complexes showed that the proposed ligand mode is possible although it does not explain the activity differences between epimers. A discussion of the structural aspects is also provided.Keywords: antimalarial; quinine; pharmacophore. INTRODUÇÃOA malária é a mais disseminada de todas as doenças infecciosas. A doença leva o indivíduo parasitado a uma anemia intensa e, em conseqüência, prejudica sua produtividade no trabalho. A doença pode ainda ter decurso fatal. Atualmente, 40% da população mundial, principalmente aquelas que vivem nos países mais pobres, vivem sob o risco de contrair malária. A málaria foi eliminada, no século XX, em vários países de clima temperado. Entretanto, ainda é encontrada em regiões tropicais e subtropicais do mundo e causa mais de 300 milhões de casos agudos e pelo menos um milhão de mortes por ano 1 . A maioria das mortes causadas por malária ocorre em crianças da África. O Brasil está entre os maiores focos de malária no mundo 2 .Os agentes etiológicos da malária humana são protozoários do gênero Plasmodium, compreendendo quatro espécies: P. falciparum, P. vivax, P. ovale e P. malariae. Os vetores são mosquitos do gênero Anopheles 3 . No homem, o ciclo biológico inicia-se com a picada do mosquito infectado que injeta na corrente sangüínea o parasita. O Plasmodium invade as células do fígado e ali se multiplica. Estas células são rompidas e o parasita cai na corrente sangüínea, indo infectar os eritrócitos. Dentro dos eritrócitos os parasitas se desenvolvem, dando origem a merozoítos que são liberados no sangue com lise destas células. A destruição cíclica dos eritrócitos e liberação do pigmento malárico levam ao acesso malárico. Do córtex do tronco e da raiz de espécies de Cinchona sp (quina), árvores naturais dos Andes, são extraídos mais de vinte alcalóides, dentre os quais dois pares de diastereoisômeros, quinina e quinidina, cinchonina e cinchonidina, têm atividade antimalárica. Tais alcalóides existem também na forma epimérica: epiquinina e epiquinidina, epicinchonina e epicinchonidina, que são inativos. Na Tabela 1 estão relatadas as atividades in vitro (IC50) da quinina, quinidina, epiquinina e epiquinidina frente a cepas de P. falciparum suceptíveis e resistentes à cloroquina 4 . Até a 2 a Guerra Mundial, a quinina (Figura 1) era o único agente antiparas...
Chagas disease is a potentially life-threatening illness caused by the flagellate protozoan Trypanosoma cruzi. In Brazil, benznidazole is the only drug available for the treatment of Chagas disease, but it has toxic side effects and is only active in the acute phase of the illness (Urbina 1999). With such an unfavourable treatment, the development of new drugs to fight Chagas disease becomes increasingly important.Because nitroaromatics have been found to be active against T. cruzi (Maya et al. 2003), we decided to evaluate the trypanocidal activity of a metronidazole (MTZ) analogue [1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I)] (Fig. 1) previously synthesised in our laboratory (Busatti et al. 2007) and its beta-cyclodextrin (β-CD) inclusion complex. We also investigated the differences in toxicity between free MTZ-I and its β-CD inclusion complex. It has been well demonstrated that inclusion complexes decrease the toxic effect of some therapeutic agents (Corrêa et al. 2005). Furthermore, the complexation of MTZ-I with CD may improve the bioavailability of MTZ-I by enhancing its water solubility.The solubility of the complex was evaluated in relation to MTZ-I with a phase solubility study. The phase solubility diagram of MTZ-I and β-CD was obtained by plotting the changes in guest solubility as a function of β-CD concentration. The solubility curve can be classified as a B s curve according to Higuchi and Connors (1965). The complex exhibits higher solubility than the guest molecule, but its limit was reached within the CD concentration ranges that were tested. Increasing the amount of available CD-molecules did not lead to a rise in solubility. However, the MTZ-I solubility increased considerably with an equimolar ratio of MTZ-I:β-CD.The solid-state inclusion complex was characterised using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). A comparison between the IR spectra of MTZ-I, β-CD, MTZ-I and β-CD in a simple 1:1 physical mixture (PM) and MTZ-I and β-CD as a complex shows some significant changes in the shape and position of the absorbance bands of the MTZ-I functional groups. Analysis of the IR spectra of the inclusion complexes revealed the most frequent changes to be in the range of 700-660 cm -1 , which were interpreted as the band corresponding to the vibration of the C-I bond. Differences were also found in the 1,526 and 1,356 cm -1 regions, which were attributed to the skeleton vibrations of the C-NO 2 group. Less pronounced changes were observed in the IR spectrum of the PM. The DSC thermal behaviours of MTZ-I, β-CD, the MTZ-I:β-CD complex and the MTZ-I:β-CD PM were also studied. The DSC curve for MTZ-I showed a typical pure crystalline substance profile with a sharp endothermic peak at 101.2ºC. The DSC curve of β-CD showed a broad endothermic peak in the range of 75-85ºC, which can be attributed to desolvation, followed by a small endothermic peak at 220.16ºC. The formation of an inclusion complex was suggested by the absence of a melting endothermic peak for MTZ-I in...
Drug development is among the topics studied in the pharmaceutical chemistry course for pharmacy undergraduates of Universidade Federal de Minas Gerais, Brazil. Computational advances in the last 20 years together with the availability of user-friendly software have promoted the development of simple computer-assisted molecular-modeling experiments for bioactive molecules. The knowledge of the specific stereochemistry of active sites for enzymes and some receptor sites justifies the study of drug conformations capable of interacting with these sites. Only a single conformation from the many possible conformations of a flexible molecule can bind to the receptor site. We report a procedure to perform conformational analysis using the systematic search method and the superimposition of two bioactive molecules, acetylcholine and muscarine. The undergraduate students individually perform the proposed procedure using a personal computer.
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