Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The low permeation of antimycobacterial agents and their difficult access to infected macrophages necessitate long-term use of high drug doses. Liposomes preferentially accumulate in macrophages, increasing the efficacy of antibiotics against intracellular parasites. In the present work, several rifabutin (RFB) liposomal formulations were developed and characterised and their in vivo profile was compared with free RFB following intravenous administration. With the RFB liposomal formulations tested, higher concentrations of the antibiotic were achieved in liver, spleen and lungs 24h post administration compared with free RFB. The concentration of RFB in these organs was dependent on the rigidity of liposomal lipids. The liposomal RFB formulation prepared with dipalmitoyl phosphatidylcholine:dipalmitoyl phosphatidylglycerol (DPPC:DPPG) was the most effective and was selected for biological evaluation in a mouse model of disseminated TB. Compared with mice treated with free RFB, mice treated with the DPPC:DPPG RFB formulation exhibited lower bacterial loads in the spleen (5.53 log(10) vs. 5.18 log(10)) and liver (5.79 log(10) vs. 5.41 log(10)). In the lung, the level of pathology was lower in mice treated with encapsulated RFB. These results suggest that liposomal RFB is a promising approach for the treatment of extrapulmonary TB in human immunodeficiency virus co-infected patients.

No abstract

No abstract

Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer’s disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2 = 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

This article examines communication practices, specific genres and audio-visual narratives developed by Brazilian video activists in the context of the protests against the FIFA World Cup competition in 2014. Analysing 170 videos produced between June and July 2014, using digital methods, audio-visual analysis and the Lilleker and Vedel scheme crossed with the Carpentier model to analyse political participation, we try to reveal what level of participation these videos represent and to discover their political nature, classifying them by level of participation. In addition, this article will attempt to highlight that the videos worked as a source of information, debate and deliberation, promoting participation, which could generate more empowerment and participation if the activists improved contextualization and the quality of the narrative.

Malaria is one of the most important tropical diseases; the use of amodiaquine as a current chemotherapy in the treatment of malaria has shown some problems such as hepatotoxicity and agranulocytosis. In this work we present the rational design, synthesis, and biological evaluation (antimalarial activity, cytotoxicity and genotoxicity) of four new fluoroamodiaquine analogues. The results showed significant correlation between MolDock score and IC 50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC 50 against Plasmodium falciparum W2 strain (0.9 and 0.8 µM, respectively) and an excellent cytotoxicity profile. The present study revealed no mutagenicity or genotoxicity for the analogues. Confirming our docking results, the molecular dynamics showed that compound 7b remains stably bound to the heme group by means of π-stacking interactions between quinoline and the porphyrin ring. Based on these findings, this study may prove to be an efficient approach for the rational design of hemozoin inhibiting compounds to treat malaria.Key words docking; molecular dynamics; molecular modeling; antimalarial Malaria is one of the most important tropical diseases, affecting 97 countries. It is an infectious disease caused by five species of Plasmodium genus protozoa, from which the P. falciparum is the most lethal in humans. There were approximately 198 million cases of malaria reported in 2013, and an estimated number of 584000 deaths, mainly in African subSaharan countries.1)The chemotherapy combination of artesunate and amodiaquine (ASAQ) is currently the treatment recommended by WHO. However, recent reports show that P. falciparum has become resistant to these chemotherapeutic agents. In addition, the use of amodiaquine (AQ) (Fig. 1) has shown some problems such as hepatotoxicity and agranulocytosis.2-4) This is a result of the biotransformation that occurs in the liver by CYP450 enzymes, which generates a reative quinoneimine metabolite, the amodiaquine quinone imine (AQQI) 5) (Fig. 1). This metabolite binds irreversibly to cellular macromolecules, leading to cell death by oxidation and, probably, to direct toxicity as well as immune-mediated hypersensitivity reactions.6,7) The mechanism of action of AQ and other 4-aminoquinolines is based on the inhibition of the parasite's mechanism of detoxification of heme, namely, the inclusion of free heme into hemozoin. By doing so, AQ increases the concentration of free heme inside the host cell acidic digestive vacuole, killing the parasite by oxidative stress. [8][9][10][11][12][13] The design of new amodiaquine derivatives with reduced toxicity and increased activity is a current matter of study.14-17) It's already well established in the literature that the fluorine insertion in this series is favorable to reduce the hepatotoxicity, by forming new compounds that are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo. 2,3,17,18) O'Neill et al. demonstrated that the 4′-hydroxyl group could b...

A molecular modeling study was applied to a data set of 21 analogues (2a-2u) of amodiaquine (2) exhibiting remarkable in vitro activity against the chloroquine-and pyrimethamine-resistant Plasmodium falciparum K1 strain (Guglielmo et al. in Eur J Med Chem 44:5071-5079, 2009). Attempting to correlate structural features with the antiparasitic activity, quantum chemical properties were calculated. In silico ADMET studies were conducted in order to recognize and find the most promising compounds with the potential of becoming new antimalarial agents. The binding mode to the heme group was studied by molecular docking, and the interactions observed in the ligand-heme complex of one of the highly active (2p) and one of the least active (2l) compounds were compared. In order to crosscheck the docking results, compound 2p was submitted to 50 ns of molecular dynamic simulation. According to that result, 2p and amodiaquine share similar binding interaction with the heme group. Additionally, a charged-assisted hydrogen bond between the protonated quinolone and the heme carboxylate group was observed. The introduction of the piperazine moiety increases the antimalarial activity profile of amodiaquine analogues by conformational features that allow these interactions. The results of this study can be used as a guide for the design of new compounds for treatment against malaria.

Este trabalho analisa dois casos de coleta de dados utilizando métodos digitais. A primeira se centra no uso de Netvizz, Nvivo y Gephi para trabalhar com dados de Facebook, YouTube e TwitCasting; e a segunda, na utilização de um scraper bot, Microsoft Excel e Tag Cloud Generator para explorar dados da plataforma Google News. As experiências demonstram que a utilização de métodos digitais na pesquisa em comunicação apresentam grande riqueza informativa e possibilidades de aprofundamento analítico que justificam seu uso, pese às debilidades apresentadas e cuidados necessários à coleta e análise.