Leishmaniasis and trypanosomiasis are major causes of morbidity and mortality in both tropical and subtropical regions of the world. The current available drugs are limited, ineffective, and require long treatment regimens. Due to the high dependence of trypanosomatids on glycolysis as a source of energy, some glycolytic enzymes have been identified as attractive targets for drug design. In the present work, classical TwoDimensional Quantitative Structure -Activity Relationships (2D QSAR) and Hologram QSAR (HQSAR) studies were performed on a series of adenosine derivatives as inhibitors of Leishmania mexicana Glyceraldehyde-3-Phosphate Dehydrogenase (LmGAPDH). Significant correlation coefficients (classical QSAR, r 2 ¼ 0.83 and q 2 ¼ 0.81; HQSAR, r 2 ¼ 0.91 and q 2 ¼ 0.86) were obtained for the 56 training set compounds, indicating the potential of the models for untested compounds. The models were then externally validated using a test set of 14 structurally related compounds and the predicted values were in good agreement with the experimental results (classical QSAR, r

Candida albicans (CA) é considerado como o principal patógeno oportunista em pacientes imunossuprimidos. A maior parte dos fármacos disponíveis para o tratamento de cepas resistentes são altamente tóxicos ou ineficazes. Uma forma de amenizar esse cenário seria através de modificações na estrutura de derivados de azóis que resultassem no aumento da potência e seletividade. Visando esclarecer quais propriedades químicas e estruturais são importantes para atividade antifúngica de derivados de azol, estudos de QSAR 2D clássico e holograma QSAR (HQSAR) foram realizados para um conjunto diverso de 52 derivados de bifonazol com atividade antifúngica. Os descritores topológicos utilizados nos estudos de QSAR 2D clássico originaram modelos com baixa consistência interna (r 2 = 0,38, q 2 = 0,27) e poder preditivo nulo (r 2 pred = −0,6). Por outro lado, a utilização de hologramas moleculares possibilitou a criação de modelos de HQSAR robustos (r 2 = 0,92, q 2 = 0,65) e com bom poder preditivo (r 2 pred = 0,79).Candida albicans (CA) has been identified as the major opportunistic pathogen in immunosuppressed patients. Most of currently available drugs are either highly toxic or becoming ineffective against resistant strains. An approach to overcome this burden relies on azole derivatives with increased potency and selectivity. Aiming at shedding some light on structural and chemical features that are important for the antifungal activity of azole derivatives, classical 2D QSAR and hologram QSAR (HQSAR) studies were performed for a diverse set of 52 bifonazole derivatives with antifungal activity. Topological descriptors, employed in Classical QSAR studies, resulted in models with low correlation (r 2 = 0.38, q 2 = 0.27) and lack of predictive power (r 2 pred = −0.6). On the other hand molecular holograms afforded HQSAR models with good correlation coefficients (r 2 = 0.92, q 2 = 0.65) and good predictive ability (r 2 pred = 0.79).

Human African trypanosomiasis, Chagas disease, and leishmaniasis are human infections caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania. Besides their severity and global impact, treatments are still challenging. Currently available drugs have important limitations, highlighting the urgent need to develop new drugs. Phosphoglucose isomerase (PGI) is considered a promising target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis. Herein, we describe the identification of new nonphosphorylated inhibitors of Leishmania mexicana PGI ( LmPGI), with the potential for the development of antiparasitic drugs. A fluorescence-based high-throughput screening (HTS) assay was developed by coupling the activities of recombinant LmPGI with glucose-6-phosphate dehydrogenase and diaphorase. This coupled assay was used to screen 42,720 compounds from ChemBridge and TimTec commercial libraries. After confirmatory assays, selected LmPGI inhibitors were tested against homologous Trypanosoma cruzi and humans. The PGI hits are effective against trypanosomatid PGIs, with IC values in the micromolar range, and also against the human homologous enzyme. A computational analysis of cavities present on PGI's crystallographic structure suggests a potential binding site for the proposed mixed-type inhibition mechanism.

Moniliophthora perniciosa, o agente causal da vassoura-de-bruxa do cacaueiro, diminuiu significativamente a produção de cacau, especialmente no estado da Bahia, a maior região produtora de cacau do continente americano. As formas de controle desenvolvidas até o momento têm baixa eficiência. Derivados de azol são ativos tanto in vitro quanto in loco contra M. perniciosa, porém não há um estudo sistemático sobre a atividade dos azóis contra este fitopatogeno. Dados biológicos, obtidos em um ensaio padronizado, foram utilizados para criação de modelos quimiométricos, que destacam características físico e estruturais importantes para a atividade fungicida de derivados de azol frente a M. perniciosa. De acordo com os modelos de PCA e SIMCA, características eletrônicas, representadas pelos descritores BEHe3 e JGI4, paralelamente à possibilidadde de realizar ligações de H e ausência de átomos de cloro, distantes de 6-8 ligações dos nitrogênios do anel azólico, parecem contribuir para atividade fungicida dos compostos estudados Moniliophthora perniciosa, the causal agent of witches' broom disease in Theobroma cacao, significantly decreased cacao production, especially in Bahia State, the largest cocoa producing of the American continent. Control programs developed so far have low efficiency. Azole derivatives are active both in vitro and in loco against M. perniciosa, however there is no comprehensive study on the activity of azoles against this phytopatogen. Standardized in vitro biological data were employed to develop supervised and unsupervised chemometric models that highlight physicochemical and structural features that are crucial for azole's fungicidal activity against M. perniciosa. Thus, PCA and SIMCA models suggest that electronegativity (BEHe3) and dipolar moment (JGI4), as well as H-bonding to M. pernciosa's lanosterol 14α-desmethylase active site and lack of Cl atoms 6 to 8 bonds from the azole's nitrogen atoms play a major role to azoles' fungicide activity.

Recebido em 22/5/12; aceito em 21/7/12; publicado na web em 15/10/12Our study reports the extraction and isolation of a new phaeophytin derivative 15 1 -hydroxy-(15 1 -S)-porphyrinolactone, designated anamariaine (1) herein, isolated from the chloroform fraction of aerial parts of Thyrsacanthus ramosissimus Moric. along with the known 15 1 -ethoxy-(15 1 -S)-porphyrinolactone (2). These compounds were identified by usual spectroscopic methods. Both compounds were subjected to in vitro (inhibitory activity) tests by means of supercoiled DNA relaxation techniques and were shown to display inhibitory activity against human DNA topoisomerase II-a at 50 µM. Interconversion of these two pigments under the mild conditions of the isolation techniques should be highly unlikely but cannot be entirely ruled out.

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Chagas disease, an infectious condition caused byTrypanosoma cruzi, lacks treatment with drugs with desired efficacy and safety profiles. To address this unmet medical need, a set of trypanocidal compounds were identified through a large multicenter phenotypic-screening initiative and assembled in the GSK Chagas Box. In the present work, we report the screening of the Chagas Box against T. cruzi malic enzymes (MEs) and the identification of three potent inhibitors of its cytosolic isoform (TcMEc). One of these compounds, TCMDC-143108 (1), came out as a nanomolar inhibitor of TcMEc, and 14 new derivatives were synthesized and tested for target inhibition and efficacy against the parasite. Moreover, we determined the crystallographic structures of TcMEc in complex with TCMDC-143108 (1) and six derivatives, revealing the allosteric inhibition site and the determinants of specificity. Our findings connect phenotypic hits from the Chagas Box to a relevant metabolic target in the parasite, providing data to foster new structure−activity guided hit optimization initiatives.