Arturene Maria Lino Carmo

4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents.

The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of β-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents.

Effect of 1,2,3-triazole salts, non-classical bioisosteres of miltefosine, on Leishmania amazonensis

Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0μM (0.9, 0.8 and 1.0μM on L. amazonensis-WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50=115.9μM) being more destructive to the intracellular parasites (selectivity index>115). Promastigotes and intramacrophage amastigotes treated with dhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis.

Increased susceptibility to Strongyloides venezuelensis in mice due to Mycobacterium bovis co-infection which modulates production of Th2 cytokines

An estimated quarter of the worlds population possesses an infection caused by gastrointestinal nematodes, which induce a Th2 type immune response. Concomitant infection of nematodes with Mycobacterium tuberculosis, which induces a predominantly Th1 type response, is very frequent in tropical and subtropical regions. This study examined immune responses of BALB/c mice infected with Strongyloides venezuelensis and then co-infected with Mycobacterium bovis. The number of worms in the intestine, eggs in feces, cytokine production in lungs and intestine and the expression of CD80, CD86, CTLA-4 and CD28 cell markers on pulmonary cells were analysed. Our results indicate that co-infected mice had an increased parasite burden, which correlates with elevated IFN-gamma and IL-10 cytokine production and decreased IL-4 and IL-13. Moreover, decreased expression of CD80 and increased expression of CTLA-4 were observed in co-infected mice. Our data point out that susceptibility to Strongyloides venezuelensis infection is increased by Mycobacterium bovis co-infection, resulting in higher parasite survival.

Synthesis of 1,2,3-triazolium-based ionic liquid and preliminary pretreatment to enhance hydrolysis of sugarcane bagasse

Ionic liquids (ILs) are salts which are liquid at low temperatures, typically with melting points under 100 oC. In recent years, the properties of many ILs have been extensively studied and have been considered as green solvents capable of replacing traditional organic solvents. Herein, ILs derived from triazole have been synthesized, thus solubility in different solvents increases with the dielectric constant of the considered solvents. Three novel 1,2,3-triazolium-based were used for the pretreatment of sugarcane bagasse. The effect of this pretreatment on lignocellulosic biomass was analyzed by scanning electron microscopy, showing an increase in the exposure surface of the bagasse samples as structural changes in the fiber.

Modulatory Effects of 6‐Carboxymethylthiopurine on Activated Murine Macrophages

The immunological activity of macrophages against pathogens in hosts includes the phagocytosis and the production of nitric oxide. We report herein the investigation of the effect of 6‐carboxymethylthiopurine on nitric oxide production by murine macrophages as well as its effect on the cell viability and proliferation after stimulus with Mycobacterium bovis bacille Calmette–Guérin, interferon‐gamma or a combination of both. J774A.1 macrophages stimulated or not by bacille Calmette–Guérin (20 μg/mL), interferon‐gamma or both, were cultured in the presence of 6‐carboxymethylthiopurine (125, 250 and 500 μm). Nitric oxide production was measured by the Griess method and cell viability/proliferation by the diphenyltetrazolium assay [3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide]. We observed an increase of J774A.1 cell proliferation after stimulus with bacille Calmette–Guérin at 125, 250 and 500 μm (69.1, 124.0 and 89.7%, respectively) and with interferon‐gamma at 125 and 250 μm (64.8% and 61.7%, respectively) (p < 0.05). In all cultures treated with 6‐carboxymethylthiopurine, interferon‐gamma‐activated nitric oxide production by J774A.1 cells decreased as well as when subjected to interferon‐gamma plus bacille Calmette–Guérin stimuli at 500 μm (p < 0.05). Altogether these data point to an anti‐inflammatory effect of 6‐carboxymethylthiopurine on stimulated macrophages.

Synthesis, characterization, and NMR studies of 1,2,3-triazolium ionic liquids: a good perspective regarding cytotoxicity

AbstractIonic liquids (ILs) have been extensively studied and are considered green solvents capable of replacing traditional organic solvents. In this study, seven 1,2,3-triazolium derivative ILs have been synthesized. In order to study the effect of the cation nature on the ILs cytotoxicity, their structures were first identified by 1H, 13C NMR 1D, and 2D spectroscopy. DFT calculations have also been performed in a way to help to provide an insightful structural analysis from 13C NMR spectroscopy. The comparison made with the NMR experimental shifts was quite important to show that the 1,2,3-triazolium derivatives have the expected structure shown here. The in vitro cytotoxicity of ILs toward macrophages showed that among the compounds tested, five did not exhibit expressive cytotoxicity on mammalian cells. Besides the well-established relationship between the carbonic chain size of the cation and the cytotoxicity, the log P of the compounds predicts that the toxicity increases with the size of the carbon chain, demonstrating that the most cytotoxic compound is also the most lipophilic one. The low cytotoxicity effect of ILs on mammalian cells points to their potential application in large-scale by industry. Graphical abstractSeven triazolium ILs were synthesized and their in vitro cytotoxicity on murine macrophages showed a relationship with the carbonic chain size.