RESUMO
Catalytic reduction of α,ß-unsaturated ketones with MgO has been found to improve selectivity to the desired unsaturated alcohol product. Using density functional calculations, we have studied the competitive hydrogenation of C=O and C=C bonds on Mg(100) employing two α,ß-unsaturated ketones: mesityl oxide (MO) and 2-cyclohexenone (CH), with isopropanol (IPA) as hydrogen source. For both ketones, MgO promotes the formation of a six-membered cyclic transition state for selective C=O reductions via a Meerwein-Ponndorf-Verley mechanism. Similar concerted mechanism is also possible for the C=C hydrogenation following an Eley-Rideal mechanism, in which the IPA interacts directly with the adsorbed ketone. The activation barriers are smaller for C=O reduction because this bond is activated on MgO(100). The selective C=O reduction is more favorable for CH than for MO due to the tendency of CH to be perpendicularly oriented. The desorption energies of the unsaturated alcohol are lower than the subsequent C=C reductions.
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Mayaro virus (MAYV) is a neglected arthropod-borne virus found in the Americas. MAYV infection results in Mayaro fever, a non-lethal debilitating disease characterized by a strong inflammatory response affecting the joints and muscles. MAYV was once considered endemic to forested areas in Brazil but has managed to adapt and spread to urban regions using new vectors, such as Aedes aegypti, and has the potential to cause serious epidemics in the future. Currently, there are no vaccines or specific treatments against MAYV. In this study, the antiviral activity of a series of synthetic cyclic ketones were evaluated for the first time against MAYV. Twenty-four compounds were screened in a cell viability assay, and eight were selected for further evaluation. Effective concentration (EC50) and selectivity index (SI) were calculated and compound 9-(5-(4-chlorophenyl]furan-2-yl)-3,6-dimethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2))-dione (9) (EC50 = 21.5 µmol·L-1, SI = 15.8) was selected for mechanism of action assays. The substance was able to reduce viral activity by approximately 70% in both pre-treatment and post-treatment assays.
Assuntos
Infecções por Alphavirus/virologia , Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Cetonas/farmacologia , Aedes/virologia , Alphavirus/fisiologia , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/transmissão , Animais , Antivirais/química , Brasil , Avaliação Pré-Clínica de Medicamentos , Humanos , Cetonas/química , Mosquitos Vetores/virologiaRESUMO
The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or "Pathogen Box" (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 µM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.
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Methoximes are important as a class of intermediates and products, among fine chemicals and specialties. The development of a new, facile and efficient method for their synthesis is reported. The methoximes were properly accessed from the corresponding aromatic aldehydes and ketones in good to excellent yields, under mild conditions, employing the inexpensive and environmentally friendly MnCl2.4H2O as a catalyst (at low loading and without the addition of ligand), in EtOH at 50°C. The scope of the process was systematically assessed.
RESUMO
The validation of protocols for carrying out the experimental analysis of amination reactions is of paramount importance to enhance the scientific knowledge and reproducibility of results. Accordingly, in the present paper, a protocol has been proposed for the study of the amination of cyclohexanone-to-secondary amines (Diphenylamine and N-Cyclohexylaniline) over heterogeneous catalysts. The results of activity and selectivity, and the elucidation of a plausible reaction pathway were described in a parent paper. Therefore, the purpose of this document is to inform about the details of the experimental setups, the methods, and the analytical techniques to identify and quantify the reaction products. Finally, some practical and safety considerations are also included.â¢One-pot catalytic amination of cyclohexanone with aniline was performed efficiently in liquid phase on Pd/C.â¢Stirring, He atmosphere and temperature control were critical to achieve reproducible activity results.â¢Ultra-High Performance Liquid Chromatography allows identifying products and reaction intermediates, while nonane performed well as internal standard for GC-FID quantification.
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ABSTRACT Introduction: Maximum oxygen uptake is an effective indicator of the level of human cardiopulmonary function and aerobic work capacity. Observing the effects of aerobic training and formulating scientific training plans are of considerable value. Objective: To observe the effect of physical exercise on the human body's maximum oxygen uptake and arterial blood ketone body ratio. Methods: Before and after 4 weeks of physical exercise, the maximum oxygen uptake, blood lactic acid and heart rate changes, and ketone body content in the incremental load exercise experiment was measured in the human body. Results: The subjects' maximum oxygen uptake, maximum exercise load, heart rate, and blood lactic acid levels increased significantly after physical exercise. Conclusion: The human body's maximum oxygen uptake is enhanced under sports. Level of evidence II; Therapeutic studies - investigation of treatment results.
RESUMO Introdução: A captação máxima de oxigênio é um indicador eficaz do nível da função cardiopulmonar e da capacidade de trabalho aeróbico humano. A observação dos efeitos de treinos aeróbicos e a formulação de planos de treinamento científicos têm valor considerável. Objetivo: Observar o efeito do exercício físico na captação máxima de oxigênio e a proporção de corpos cetônicos e sangue arterial no corpo humano. Métodos: Antes e após exercícios físicos de quatro semanas, a captação máxima de oxigênio, ácido láctico no sangue e mudanças na frequência cardíaca, além do conteúdo de corpos cetônicos, em um experimento de carga de exercícios progressiva foram medidos no corpo humano. Resultados: A captação máxima de oxigênio, carga máxima de exercício, frequência cardíaca e níveis de ácido láctico no sangue dos indivíduos aumentaram significativamente após o exercício físico. Conclusão: A captação máxima de oxigênio aumenta com a prática de esportes. Nível de evidência II; Estudos terapêuticos - investigação de resultados de tratamento.
RESUMEN Introducción: La captación máxima de oxígeno es un indicador eficaz del nivel de la función cardiopulmonar y de la capacidad de trabajo aeróbico humano. La observación de los efectos de entrenamientos aeróbicos y la formulación de planes de entrenamiento científicos tiene valor considerable. Objetivo: Observar el efecto del ejercicio físico en la captación máxima de oxígeno y la proporción de cuerpos cetónicos y sangre arterial en el cuerpo humano. Métodos: Se midió, en el cuerpo humano, antes y después de ejercicios físicos de 4 semanas, la captación máxima de oxígeno, ácido láctico en la sangre y cambios en la frecuencia cardíaca, además del contenido de cuerpo cetónicos, en un experimento de carga progresiva. Resultados: La captación máxima de oxígeno, carga máxima de ejercicio, frecuencia cardíaca y niveles de ácido láctico en la sangre de los individuos aumentaron significativamente tras el ejercicio físico. Conclusión: La captación máxima de oxígeno aumenta con la práctica de deportes. Nivel de evidencia II; Estudios terapéuticos - investigación de resultados de tratamiento.
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We described herein a selective method to prepare α-organylthio esters and α-organylthio ketones by the reaction of ß-keto esters with sodium S-benzyl sulfurothioate or sodium S-alkyl sulfurothioate (Bunte salts) under basic conditions in toluene as the solvent at 100 °C. When 4 equivalents of a base were used, a series of differently substituted α-thio esters were obtained with up to 90% yield. On the other hand, employing 2 equivalents of a base, α-thio ketones were achieved after 18 h under air. Furthermore, after a shorter reaction time, the isolation of keto-enol tautomers was possible, revealing them as significant intermediates for the mechanism elucidation.
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The importance of gem-difunctionalized ketones is represented by their broad applications across chemical boundaries over recent years. The interesting reactivities that this class of compounds possess have made them ideal building blocks to access high-value organic molecules. Furthermore, the gem-difunctionalized ketone moiety has featured in numerous bioactive molecules. For these reasons, a plethora of routes to access such significant molecules have been developed by research groups worldwide - this account looks at delineating the synthesis of gem-difunctionalized ketones from carbonyl substrates, diazo compounds, sulfur ylides and alkynyl reactants.
RESUMO
Palladium-catalyzed cross-coupling of bile acids with 2-furanylboronic acid produced steroid furanyl ketones in low yields. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques.
Assuntos
Ácidos e Sais Biliares/química , Ácidos Borônicos/química , Furanos/química , Paládio/química , Esteroides/química , Esteroides/síntese química , Catálise , Técnicas de Química Sintética , EstereoisomerismoRESUMO
Zika Virus (ZIKV), an arbovirus that belongs to the Flaviviridae family, has become a global concern since its outbreak in the Americas in 2015. With symptoms similar to other Flavivirus as Dengue and Yellow Fever viruses, infections by ZIKV have also been related to several neurological complications such as microcephaly in newborns and Guillain-Barre syndrome. Considering the high prevalence of ZIKV infection in certain areas, the risks that the virus poses to fetal brain development, and the fact that there is no vaccine or specific prophylaxis available, an effective treatment capable of preventing the infection is of potential interest. Therefore, in the present investigation, the antiviral activity on ZIKV of a group of xanthenodiones and intermediate ketones involved in their synthesis was evaluated for the first time. It was found that the compound 2-(2,6-dichlorobenzylidene)cyclohexane-1,3-dione 27 was able to completely inhibit the viral infection of Vero cells as well as to significantly reduce viral load in the brains of newborn Swiss mice. These effects are related to a direct interaction of the compound with the viral particle, blocking the viral adsorption.
Assuntos
Antivirais/química , Antivirais/farmacologia , Sistema Nervoso Central/virologia , Infecção por Zika virus/tratamento farmacológico , Zika virus/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Simulação por Computador , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cetonas/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. OBJECTIVE: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. METHODS: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and ß-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C - APT, 1H x 1H - COSY, HSQC and HMBC], IR and mass spectrometry analysis. RESULTS: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. CONCLUSION: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.
Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Indolquinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Humanos , Indolquinonas/síntese química , Indolquinonas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
A continuous flow approach for the synthesis of α-acyloxy ketone derivatives from the corresponding arylglyoxals, isocyanides, and carboxylic acids is described. The target products were obtained in excellent yields in short residence times and with high purities via the first transcription of the microwave-to-flow paradigm to the isocyanide-based Passerini reaction. Furthermore, this methodology allowed a 10-fold scale-up using the same experimental conditions initially established.
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The increasing detection of virulent and/or multidrug resistant bacterial strains makes necessary the development of new antimicrobial agents acting through novel mechanisms and cellular targets. A good choice are molecules aimed to interfere with the cell division machinery or divisome, which is indispensable for bacterial survival and propagation. A key component of this machinery, and thus a good target, is FtsZ, a highly conserved GTPase protein that polymerizes in the middle of the cell on the inner face of the cytoplasmic membrane forming the Z ring, which acts as a scaffold for the recruitment of the divisome proteins at the division site. In this work, we tested the inhibitory effect of five diaryl naphtyl ketone (dNAK) molecules on the in vitro polymerization of both Escherichia coli and Bacillus subtilis FtsZ (EcFtsZ and BsFtsZ, respectively). Among these compounds, dNAK 4 showed the strongest inhibition of FtsZ polymerization in vitro, with an IC50 of 2.3 ± 0.06 µM for EcFtsZ and 9.13 ± 0.66 µM for BsFtsZ. We found that dNAK 4 binds to GDP-FtsZ polymers but not to the monomer in GTP or GDP state. This led to the polymerization of short and curved filaments, rings, open rings forming clusters, and in the case of BsFtsZ, a novel cylindrical structure of stacked open rings. In vivo, dNAK 4 had almost no effect on the growth of E. coli in liquid culture, in contrast to the strong inhibitory effect observed over B. subtilis growth. The insensitivity of E. coli to this compound is probably related to the impermeability of dNAK 4 to the outer membrane. The low amount of this compound required to inhibit several of the bacterial strains tested and the lack of a cytotoxic effect at the concentrations used, makes dNAK 4 a very good candidate as a starting molecule for the development of a new antibiotic.
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Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world's population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode Caenorhabditis elegans is a formidable experimentally tractable model organism that offers key advantages in accelerating nematicide discovery. We report the screening of drug-like libraries using an overnight high-throughput C. elegans assay, based on an automated infrared motility reader. As a proof of concept, we screened the "Pathogen Box" library, and identical results to a previous screen using Haemonchus contortus were obtained. We then screened an in-house library containing a diversity of compound families. Most active compounds had a conjugation of an unsaturation with an electronegative atom (N, O, or S) and an aromatic ring. Importantly, we identified symmetric arylidene ketones and aryl hydrazine derivatives as novel nematicides. Furthermore, one of these compounds, (1E,2E)-1,2-bis(thiophen-3-ylmethylene)hydrazine, was active as a nematicide at 25 µm, but innocuous to the vertebrate model zebrafish at 50 µm. Our results identified novel nematicidal scaffolds and illustrate the value of C. elegans in accelerating nematicide discovery using a nonlabor-intensive automated assay that provides a simple overnight readout.
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The formation of amide bonds is one of the most stimulating emerging areas in organic and medicinal chemistry. Amides are recognized as central building blocks in a plethora of interesting pharmaceuticals, proteins, peptides, polymers, natural products, functional materials, and biologically relevant carbocyclic or heterocyclic molecules, and they are also found in a variety of industrial fields. Therefore, a review of recent developments and challenges in the formation of amide bonds from carbonyl compounds is particularly important. Herein, we have scrutinized a range of metal-catalyzed and metal-free approaches for the synthesis of amides from aldehydes, ketones, and oximes. In addition, this Minireview highlights relevant mechanistic studies, as well as the potential applications of these methods in the synthesis of candidate drug molecules. We hope that the data compiled herein will encourage further progress in this notable area of chemistry research.
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We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5⯵g/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50â¯=â¯3.5⯵M; Kiâ¯=â¯4.8⯵M) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50â¯=â¯2.3⯵M; Kiâ¯=â¯0.7⯵M) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.
Assuntos
Antibacterianos/farmacologia , Benzoína/análogos & derivados , Benzoína/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Benzoína/síntese química , Domínio Catalítico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Meticilina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacosRESUMO
γ-Aminobutyric-acid receptor (GABAA-R), a membrane intrinsic protein, is activated by GABA and modulated by a wide variety of recognized drugs. GABAA-R is also target for several insecticides which act by recognition of a non-competitive blocking site. Mentha oil is rich in several ketones with established activity against various insects/pests. Considering that mint ketones are highly lipophilic, their action mechanism could involve, at least in part, a non-specific receptor modulation by interacting with the surrounding lipids. In the present work, we studied in detail the effect on membranes of five cyclic ketones present in mint plants, with demonstrated insecticide and gabaergic activity. Particularly, we have explored their effect on the organization and dynamics of the membrane, by using Molecular Dynamics (MD) Simulation studies in a bilayer model of DPPC. We performed free diffusion MD and obtained spatially resolved free energy profiles of ketones partition into bilayers based on umbrella sampling. The most favored location of ketones in the membrane corresponded to the lower region of the carbonyl groups. Both hydrocarbon chains were slightly affected by the presence of ketones, presenting an ordering effect for the methylene groups closer to the carbonyl. MD simulations results were also contrasted with experimental data from fluorescence anisotropy studies which evaluate changes in membrane fluidity. In agreement, these assays indicated that the presence of ketones between lipid molecules induced an enhancement of the intermolecular interaction, increasing the molecular order throughout the bilayer thickness.
Assuntos
Cetonas/química , Simulação de Dinâmica Molecular , Lipossomas Unilamelares/química , Ácido gama-Aminobutírico/química , Polarização de Fluorescência , Ligação de Hidrogênio , Cetonas/metabolismo , Temperatura , Termodinâmica , Lipossomas Unilamelares/metabolismoRESUMO
A one-pot alkylation-halogenation of ketosulfoxonium ylides in the presence of alkyl halides is described. The method furnishes several gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) in good yields. Replacing alkyl halides with a mixture of electrophilic halogen species and various halide anions led to gem-dihalogenated ketones containing a combination of the same or two different halogens. Kinetic isotopic effects as well as reaction kinetic experiments give insight to the mechanism of these reactions.
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An efficient route for the synthesis of novel 7-aryl and 7-spiropyrazolo[4[Formula: see text],3[Formula: see text]:5,6]pyrido[2,3-d]pyrimidine derivatives is described. These compounds were obtained by a cyclocondensation reaction between pyrazolopyridinediamines 4 and aldehydes 5 or cyclic ketones 6 in the presence of acetic acid as catalyst. This procedure provides the desired compounds in good yields under a simple two-step methodology. The obtained compounds were evaluated as AChE inhibitors and showed weak AChe inhibition with [Formula: see text].
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Compostos de Espiro/química , Animais , Técnicas de Química Sintética , Inibidores da Colinesterase/química , Electrophorus , Pirimidinas/químicaRESUMO
A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against Leishmania infantum and Leishmania braziliensis. Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against Trypanosoma cruzi. The cytotoxicity of the active compounds on non-infected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their anti-parasitic effects. Seven thiazolidenehydrazine derivatives and ten arylideneketones had good activity against the three parasites. The IC50 values for T. cruzi and Leishmania spp. ranged from 90 nM-25 µM. Eight compounds had multi-trypanocidal activity against T. cruzi and Leishmania spp. (the etiological agents of cutaneous and visceral forms). The selectivity of these active compounds was better than the three reference drugs: benznidazole, glucantime and miltefosine. They also had low toxicity when tested in vivo on zebrafish. Trying to understand the mechanism of action of these compounds, two possible molecular targets were investigated: triosephosphate isomerase and cruzipain. We also used a molecular stripping approach to elucidate the minimal structural requirements for their anti-T. cruzi activity.