RESUMO
Fasciola hepatica is a parasitic trematode that infects livestock animals and humans, causing significant health and economic burdens worldwide. The extensive use of anthelmintic drugs has led to the emergence of resistant parasite strains, posing a threat to treatment success. The complex life cycle of the liver fluke, coupled with limited funding and research interest, have hindered progress in drug discovery. Our group has been working in drug development against this parasite using cathepsin proteases as molecular targets, finding promising compound candidates with inâ vitro and inâ vivo efficacy. Here, we evaluated hybrid molecules that combine two chemotypes, chalcones and quinoxaline 1,4-di- N-oxides, previously found to inhibit F.â hepatica cathepsin Ls and tested their inâ vitro activity with the isolated targets and the parasites in culture. These molecules proved to be good cathepsin inhibitors and to kill the juvenile parasites at micromolar concentrations. Also, we performed molecular docking studies to analyze the compounds-cathepsins interface, finding that the best inhibitors interact at the active site cleft and contact the catalytic dyad and residues belonging to the substrate binding pockets. We conclude that the hybrid compounds constitute promising scaffolds for the further development of new fasciolicidal compounds.
RESUMO
Leishmaniasis remains one of the main public health problems worldwide, with special incidence in the poorest populations. Selenium and its derivatives can be potent therapeutic options against protozoan parasites. In this work, 17 aryl selenoates were synthesized and screened against three species of Leishmania (Leishmania major, Leishmania amazonensis, and Leishmania infantum). Initial screening in promastigotes showed L. infantum species was more sensitive to selenoderivatives than the others. The lead Se-(2-selenocyanatoethyl) thiophene-2-carboselenoate (16) showed a half-maximal effective concentration of 3.07 µM and a selectivity index > 32.57 against L. infantum promastigotes. It was also the most effective of all 17 compounds, decreasing the infection ratio by 90% in L. infantum-infected macrophages with amastigotes at 10 µM. This aryl selenoate did not produce a hemolytic effect on human red blood cells at the studied doses (10-100 µM). Furthermore, the gene expression of infected murine macrophages related to cell death, the cell cycle, and the selenoprotein synthesis pathway in amastigotes was altered, while no changes were observed in their murine homologs, supporting the specificity of Compound 16 against the parasite. Therefore, this work reveals the possible benefits of selenoate derivatives for the treatment of leishmaniasis.
Assuntos
Antiprotozoários , Leishmania infantum , Leishmania mexicana , Leishmaniose , Animais , Camundongos , Humanos , Leishmaniose/tratamento farmacológico , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Expressão Gênica , Camundongos Endogâmicos BALB CRESUMO
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.
Assuntos
Doença de Alzheimer , Piperidinas , Humanos , Doença de Alzheimer/tratamento farmacológico , Acetilcolinesterase , Galantamina , AcetilcolinaRESUMO
In 2020, the WHO established the road map for neglected tropical diseases 2021-2030, which aims to control and eradicate 20 diseases, including leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions, such as those caused by Trypanosoma cruzi and Leishmania spp. infections. In this scenario, it is worth highlighting a group of natural peptide molecules (AMPs and CPPs) that are promising strategies for improving therapeutic efficacy against these neglected zoonoses, as they avoid the development of toxicity and resistance of conventional treatments. This review presents the novelties of these peptide molecules and their ability to cross a whole system of cell membranes as well as stimulate host immune defenses or even serve as vectors of molecules. The efforts of the biotechnological sector will make it possible to overcome the limitations of antimicrobial peptides through encapsulation and functionalization methods to obtain approval for these treatments to be used in clinical programs for the eradication of leishmaniosis and Chagas disease.
RESUMO
Current treatment for Chagas disease is based on only two drugs: benznidazole and nifurtimox. Compounds containing sulfur (S) in their structure have shown promising results in vitro and in vivo against Trypanosoma cruzi, the parasite causing Chagas disease. Notably, some reports show that the isosteric replacement of S by selenium (Se) could be an interesting strategy for the development of new compounds for the treatment of Chagas disease. To date, the activity against T. cruzi of three Se- containing groups has been compared with their S counterparts: selenosemicarbazones, selenoquinones, and selenocyanates. More studies are needed to confirm the positive results of Se compounds. Therefore, we have investigated S compounds described in the literature tested against T. cruzi. We focused on those tested in vivo that allowed isosteric replacement to propose their Se counterparts as promising compounds for the future development of new drugs against Chagas disease.
Assuntos
Doença de Chagas , Selênio , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Selênio/uso terapêutico , Enxofre/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêuticoRESUMO
Chagas disease (CD) is a centenarian neglected parasitosis caused by the protozoan Trypanosoma cruzi (T. cruzi). Despite the continuous efforts of many organizations and institutions, CD is still an important human health problem worldwide. A lack of a safe and affordable treatment has led drug discovery programmes to focus, for years, on the search for molecules enabling interference with enzymes that are essential for T. cruzi survival. In this work, the authors want to offer a brief overview of the different validated targets that are involved in diverse parasite pathways: glycolysis, sterol synthesis, the de novo biosynthesis of pyrimidine nucleotides, the degradative processing of peptides and proteins, oxidative stress damage and purine salvage and nucleotide synthesis and metabolism. Their structural aspects, function, active sites, etc. were studied and considered with the aim of defining molecular bases in the search for new effective treatments for CD. This review also compiles, as much as possible, all the inhibitors reported to date against these T. cruzi targets, serving as a reference for future research in this field.
Assuntos
Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Doença de Chagas/metabolismo , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.
Assuntos
Benzimidazóis/química , Desenho de Fármacos , Imidazóis/química , Bases de Mannich/química , Tripanossomicidas/síntese química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Bases de Mannich/farmacologia , Bases de Mannich/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/fisiologiaRESUMO
Chagas disease is one of the most prevalent tropical neglected diseases and causes high mortality and morbidity in endemic countries. Current treatments for this disease, nifurtimox and benznidazole, are ineffective in the chronic phase of the disease and produce severe adverse effects. Therefore, novel therapies are urgently required. The trace element selenium has an important role in human health, due to its antioxidant, antiinflammatory and pro-immune properties. Actually, its deficiency has been related to several diseases and supplementation with this element has been proven to be beneficial for multiple pathologies. Furthermore, the usefulness of organic-selenium compounds has been studied in many disorders, showing promising results. The aim of this review is to analyse the available literature regarding the role of selenium in Chagas disease in order to determine whether its use could be beneficial for the management of this pathology.
Assuntos
Doença de Chagas/tratamento farmacológico , Selênio/química , Selênio/farmacologia , Animais , Doença de Chagas/metabolismo , Humanos , Terapia de Alvo Molecular , Selênio/metabolismo , Selênio/uso terapêuticoRESUMO
The haemoflagellate protozoan Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas disease (CD), a potentially life-threatening disease. Little by little, remarkable progress has been achieved against CD, although it is still not enough. In the absence of effective chemotherapy, many research groups, organizations and pharmaceutical companies have focused their efforts on the search for compounds that could become viable drugs against CD. Within the wide variety of reported derivatives, this review summarizes and provides a global vision of the situation of those compounds that include broadly studied heterocycles in their structures due to their applications in medicinal chemistry: imidazole and benzimidazole rings. Therefore, the intention of this work is to present a compilation, as much as possible, of all the reported information, regarding these imidazole and benzimidazole derivatives against T. cruzi, as a starting point for future researchers in this field.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacologia , Animais , Benzimidazóis/uso terapêutico , Humanos , Imidazóis/uso terapêuticoRESUMO
The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.
Assuntos
Doença de Chagas/tratamento farmacológico , Bases de Mannich/farmacologia , Superóxido Dismutase/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células Cultivadas , Doença de Chagas/metabolismo , Chlorocebus aethiops , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Relação Dose-Resposta a Droga , Humanos , Injeções Intraperitoneais , Bases de Mannich/síntese química , Bases de Mannich/química , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismo , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/metabolismo , Células VeroRESUMO
Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2, 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC50) value around 5⯵M in both amastigote and trypomastigote forms of T. cruzi and SI values higher than 13, being the best value on the trypomastigote forms of the Arequipa strain (SIâ¯=â¯41.7). Moreover, 2 decreased the number of infected cells and was not genotoxic. Furthermore, its possible mechanism of action was studied through the alteration of the metabolites excreted by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase (SOD). Finally, docking studies were executed to analyze the binding mode of the studied compounds to Fe-SOD enzyme.
Assuntos
Doença de Chagas/tratamento farmacológico , Bases de Mannich/farmacologia , Tripanossomicidas/síntese química , Animais , Chlorocebus aethiops , Transtornos do Metabolismo de Glucose , Bases de Mannich/síntese química , Simulação de Acoplamento Molecular , Ligação Proteica , Superóxido Dismutase/metabolismo , Tripanossomicidas/farmacologia , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/metabolismo , Células Vero/parasitologiaRESUMO
Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.
Assuntos
Bases de Mannich/química , Bases de Mannich/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Chlorocebus aethiops , Replicação do DNA/efeitos dos fármacos , Feminino , Concentração Inibidora 50 , Bases de Mannich/metabolismo , Bases de Mannich/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Testes de Sensibilidade Parasitária , Conformação Proteica , Relação Estrutura-Atividade , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Tripanossomicidas/metabolismo , Tripanossomicidas/toxicidade , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/genética , Células VeroRESUMO
The development of safe and affordable antiparasitic agents effective against neglected tropical diseases is a big challenge of the drug discovery. The drugs currently employed have limitations such as poor efficacy, drug resistance or side effects. Thus, the search for new promising drugs is more and more crucial. Metal complexes and, in particular, organometallic compounds may expand the list of the drug candidates due to the peculiar attributes that the presence of the metal core add to the organic fragment (e.g., redox and structural features, ability to interact with DNA or protein targets, etc.). To date, most organometallic compounds tested as anti-neglected tropical diseases are based on similarities or activity of the organic ligands against other diseases or parasites and/or consist in modification of existing drugs combining the features of the metal moiety and the organic ligands. This review focuses on recent studies (2012-2017) on organometallic compounds in treating kinetoplastid-caused diseases such as Human African trypanosomiasis, Chagas disease and leishmaniasis. This field of research, however, still lacks exhaustive studies to identify of parasitic targets and quantitative structure-activity relationships for a rational drug design.
Assuntos
Antiparasitários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Leishmaniose/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiparasitários/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 µM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Óxidos/química , Análise Espectral/métodosRESUMO
Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.
Assuntos
Leishmania braziliensis/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Bases de Mannich/farmacologia , Superóxido Dismutase/metabolismo , Tripanossomicidas/farmacologia , Animais , Linhagem Celular , Bases de Mannich/química , Camundongos , Testes de Sensibilidade Parasitária , Tripanossomicidas/químicaRESUMO
The development and validation of an analytical method for the simultaneous analysis of five neutral lipids in Trypanosoma cruzi epimastigotes by GC-MS is presented in this study. The validated method meets all validation parameters for all components and the chromatographic conditions have been optimized during its development. This analytical method has demonstrated good selectivity, accuracy, within-day precision, recovery and linearity in each of the established ranges. In addition, detection and quantification limits for squalene, cholesterol, ergosterol and lanosterol have been improved and it is worth highlighting the fact that this is the first time that squalene-2,3-epoxide validation data have been reported. The new validated method has been applied to epimastigotes treated with compounds with in vitro anti-T.cruzi activity. This new methodology is straightforward and constitutes a tool for screening possible sterol biosynthesis pathway inhibitors in Trypanosoma cruzi, one of the most studied targets in Chagas disease treatment. Therefore, it is an interesting and useful contribution to medicinal chemistry research.
Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Esqualeno/análise , Esteróis/análise , Trypanosoma cruzi/química , Animais , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Esqualeno/análogos & derivados , Trypanosoma cruzi/metabolismoRESUMO
The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.
Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Meglumina/farmacologia , Compostos Organometálicos/farmacologia , Animais , Humanos , Leishmania braziliensis/metabolismo , Leishmania infantum/metabolismo , Antimoniato de Meglumina , Testes de Sensibilidade Parasitária , Selênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
It has been over a century since Carlos Chagas discovered the Trypanosoma cruzi (T. cruzi) as the causative agent of Chagas disease (CD), a neglected tropical disease with several socioeconomic, epidemiological and human health repercussions. Currently, there are only two commercialized drugs to treat CD in acute phase, nifurtimox and benznidazol, with several adverse side effects. Thus, new orally available and safe drugs for this parasitic infection are urgently required. One strategy of great importance in new drug discovery programmes is based on the search of molecules enabling to interfere with enzymes involved in T. cruzi metabolism. This review will focus on two of the most promising targets for the therapy of CD: trypanothione reductase (TR) and the iron-containing superoxide dismutase (Fe- SOD), which protect the parasite against oxidative damage by reactive oxygen species. A brief comparison of the function, mechanism of action and the active sites between T. cruzi TR and Fe-SOD with their analogues enzymes in human, glutathione reductase (GR) and the corresponding SODs, will be discussed. This review will also summarize the recent development and structure-activity relationships of novel compounds reported for their ability to selectively inhibit these targets, aiming to define molecular bases in the search for new effective treatment of CD.
Assuntos
NADH NADPH Oxirredutases/antagonistas & inibidores , Superóxido Dismutase/antagonistas & inibidores , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia , Domínio Catalítico , Doença de Chagas/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/metabolismo , Humanos , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/metabolismo , Fenotiazinas/química , Poliaminas/química , Poliaminas/uso terapêutico , Relação Estrutura-Atividade , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.