RESUMEN
INTRODUCTION: Chagas disease is caused by the protozoan Trypanosoma cruzi and is clinically divided into acute and chronic phases. Chronic Chagas cardiomyopathy is the most studied manifestation of the disease. Vitamin D deficiency has been suggested as a risk factor for cardiovascular disease. No studies demonstrate the action of this hormone in the cells of patients with chronic Chagas heart disease. OBJECTIVE: To evaluate the in vitro immunomodulatory effect of vitamin D on peripheral blood mononuclear cells of patients with the different chronic clinical forms of Chagas disease. Evaluating vitamin D's in vitro effect on blood cells by producing cytokines. METHODS: Thirteen patients of the undetermined form (IND), 13 of the mild cardiac form (CARD1) and 14 of the severe cardiac form (CARD2) of Chagas disease, and 12 with idiopathic heart disease (CARDid) were included. The cells obtained from peripheral blood were treated in vitro with vitamin D (1 × 10-7 M) for 24 h and cytokines were dosed in the culture supernatant. RESULTS: Although it was not possible to demonstrate statistically significant differences between the groups studied, our data showed that the cells treated with vitamin D modify (p < .05) the production of interferon-γ (IFN-γ) (decrease in IND), tumor necrosis factor-α (TNF-α) (decreased in CARD1 and CARDid), interleukin (IL)-6 (increased in all groups), and IL-10 (decreased in CARD1, CARD2, and CARDid) when compared to untreated cells. CONCLUSION: In vitro treatment with vitamin D distinctly modulated the production of cytokines by mononuclear cells of peripheral blood among patients with chronic and indeterminate cardiac clinical forms of Chagas disease.
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Citocinas , Leucocitos Mononucleares , Vitamina D , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Vitamina D/farmacología , Masculino , Femenino , Persona de Mediana Edad , Citocinas/metabolismo , Adulto , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/inmunología , Enfermedad Crónica , Trypanosoma cruzi/inmunología , Trypanosoma cruzi/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Anciano , Células CultivadasAsunto(s)
Aspirina , Enfermedad de Chagas , Lipoxinas , Trypanosoma cruzi , Aspirina/farmacología , Aspirina/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/genética , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/prevención & control , Lipoxinas/metabolismo , Ratones , Modelos Animales de Enfermedad , HumanosRESUMEN
BACKGROUND: Maternal-foetal transmission of Chagas disease (CD) affects newborns worldwide. Although Benznidazole and Nifurtimox therapies are the standard treatments, their use during pregnancy is contra-indicated. The effectiveness of trypanocidal medications in preventing congenital Chagas Disease (cCD) in the offsprings of women diagnosed with CD was highly suggested by other studies. METHODS: We performed a systematic review and meta-analysis of studies evaluating the effectiveness of treatment for CD in women of childbearing age and reporting frequencies of cCD in their children. PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases were systematically searched. Statistical analysis was performed using Rstudio 4.2 using DerSimonian and Laird random-effects models. Heterogeneity was examined with the Cochran Q test and I2 statistics. A p-value of <0.05 was considered statistically significant. RESULTS: Six studies were included, comprising 744 children, of whom 286 (38.4%) were born from women previously treated with Benznidazole or Nifurtimox, trypanocidal agents. The primary outcome of the proportion of children who were seropositive for cCD, confirmed by serology, was signigicantly lower among women who were previously treated with no congenital transmission registered (OR 0.05; 95% Cl 0.01-0.27; p = 0.000432; I2 = 0%). In women previously treated with trypanocidal drugs, the pooled prevalence of cCD was 0.0% (95% Cl 0-0.91%; I2 = 0%), our meta-analysis confirms the excellent effectiveness of this treatment. The prevalence of adverse events in women previously treated with antitrypanocidal therapies was 14.01% (95% CI 1.87-26.14%; I2 = 80%), Benznidazole had a higher incidence of side effects than Nifurtimox (76% vs 24%). CONCLUSION: The use of trypanocidal therapy in women at reproductive age with CD is an effective strategy for the prevention of cCD, with a complete elimination of congenital transmission of Trypanosoma cruzi in treated vs untreated infected women.
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Enfermedad de Chagas , Transmisión Vertical de Enfermedad Infecciosa , Nifurtimox , Nitroimidazoles , Tripanocidas , Humanos , Femenino , Tripanocidas/uso terapéutico , Tripanocidas/efectos adversos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/prevención & control , Enfermedad de Chagas/congénito , Enfermedad de Chagas/transmisión , Embarazo , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Nifurtimox/uso terapéutico , Nifurtimox/efectos adversos , Nitroimidazoles/uso terapéutico , Nitroimidazoles/efectos adversos , Estudios Observacionales como Asunto , Recién Nacido , Adulto , Trypanosoma cruzi/efectos de los fármacos , Complicaciones Parasitarias del Embarazo/prevención & control , Complicaciones Parasitarias del Embarazo/tratamiento farmacológicoRESUMEN
Cyclodextrins are ring-shaped sugars used as additives in medications to improve solubility, stability, and sensory characteristics. Despite being widespread, Chagas disease is neglected because of the limitations of available medications. This study aims to review the compounds used in the formation of inclusion complexes for the treatment of Chagas disease, analyzing the incorporated compounds and advancements in related studies. The databases consulted include Scielo, Scopus, ScienceDirect, PubMed, LILACS, and Embase. The keywords used were "cyclodextrin AND Chagas AND disease" and "cyclodextrin complex against Trypanosoma cruzi". Additionally, a statistical analysis of studies on Chagas disease over the last five years was conducted, highlighting the importance of research in this area. This review focused on articles that emphasize how cyclodextrins can improve the bioavailability, therapeutic action, toxicity, and solubility of medications. Initially, 380 articles were identified with the keyword "cyclodextrin AND Chagas disease"; 356 were excluded for not being directly related to the topic, using the keyword "cyclodextrin complex against Trypanosoma cruzi". Over the last five years, a total of 13,075 studies on Chagas disease treatment were found in our literature analysis. The studies also showed interest in molecules derived from natural products and vegetable oils. Research on cyclodextrins, particularly in the context of Chagas disease treatment, has advanced significantly, with studies highlighting the efficacy of molecules in cyclodextrin complexes and indicating promising advances in disease treatment.
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Enfermedad de Chagas , Ciclodextrinas , Trypanosoma cruzi , Enfermedad de Chagas/tratamiento farmacológico , Ciclodextrinas/química , Ciclodextrinas/uso terapéutico , Humanos , Trypanosoma cruzi/efectos de los fármacos , Animales , Tripanocidas/uso terapéutico , Tripanocidas/química , Tripanocidas/farmacologíaRESUMEN
The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18-23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19-21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 µM.
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Imidazoles , Leishmania donovani , Tiadiazoles , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Leishmania donovani/efectos de los fármacos , Leishmania donovani/crecimiento & desarrollo , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.
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Cisteína Endopeptidasas , Simulación del Acoplamiento Molecular , Proteínas Protozoarias , Triazoles , Trypanosoma cruzi , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Cisteína Endopeptidasas/química , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/química , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores de Cisteína Proteinasa/síntesis química , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Diseño Asistido por Computadora , Diseño de Fármacos , Humanos , Estructura Molecular , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Enfermedad de Chagas/tratamiento farmacológicoRESUMEN
A new polyketide, cladoic acid, was isolated from a fungus of the genus Cladosporium. The structure of the highly oxygenated trans-decalin ring with an all-E triene side chain was elucidated by extensive spectroscopic analysis. The unique chair/twist-boat conformation of the trans-decalin core and the flexibility of the B-ring were demonstrated by computer-aided conformational analysis. Cladoic acid was active against Trypanosoma cruzi and inhibited the proliferation of amastigotes and epimastigotes with IC50 values of 27 and 46 µM, respectively, but it did not show any appreciable activity against P388 murine leukemia cells, bacteria, or fungi, indicating it is a potential candidate for drug development against Chagas disease.
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Cladosporium , Policétidos , Trypanosoma cruzi , Cladosporium/química , Trypanosoma cruzi/efectos de los fármacos , Animales , Policétidos/farmacología , Policétidos/química , Policétidos/aislamiento & purificación , Estructura Molecular , Ratones , Concentración 50 Inhibidora , Leucemia P388 , Enfermedad de Chagas/tratamiento farmacológicoRESUMEN
Introduction: Chagas disease, caused by the Trypanosoma cruzi parasite infection, is a potentially life-threatening neglected tropical disease with a worldwide distribution. During the chronic phase of the disease, there exists a fragile balance between the host immune response and parasite replication that keeps patients in a clinically-silent asymptomatic stage for years or even decades. However, in 40% of patients, the disease progresses to clinical manifestations mainly affecting and compromising the cardiac system. Treatment is recommended in the chronic phase, although there are no early markers of its effectiveness. The aim of this study is to identify differential expression changes in genes involved in the immune response in antigen-restimulated PBMC from chronic patients with Chagas disease due to benznidazole treatment. Methods: Thus, high-throughput real-time qPCR analysis has been performed to simultaneously determine global changes in the expression of 106 genes involved in the immune response in asymptomatic (IND) and early cardiac manifestations (CCC I) Chagas disease patients pre- and post-treatment with benznidazole. Results and discussion: The results revealed that 7 out of the 106 analyzed genes were differentially expressed (4 up- and 3 downregulated) after treatment in IND patients and 15 out of 106 (3 up- and 12 downregulated) after treatment of early cardiac Chagas disease patients. Particularly in CCC I patients, regulation of the expression level of some of these genes towards a level similar to that of healthy subjects suggests a beneficial effect of treatment and supports recommendation of benznidazole administration to early cardiac Chagas disease patients. The data obtained also demonstrated that both in asymptomatic patients and in early cardiac chronic patients, after treatment with benznidazole there is a negative regulation of the proinflammatory and cytotoxic responses triggered as a consequence of T. cruzi infection and the persistence of the parasite. This downregulation of the immune response likely prevents marked tissue damage and healing in early cardiac patients, suggesting its positive effect in controlling the pathology.
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Enfermedad de Chagas , Nitroimidazoles , Trypanosoma cruzi , Humanos , Nitroimidazoles/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/inmunología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/genética , Adulto , Masculino , Femenino , Persona de Mediana Edad , Tripanocidas/uso terapéutico , Tripanocidas/farmacología , Leucocitos Mononucleares/inmunología , Enfermedad Crónica , Perfilación de la Expresión Génica , Voluntarios Sanos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Neglected Tropical Diseases are a significant concern as they encompass various infections caused by pathogens prevalent in tropical regions. The limited and often highly toxic treatment options for these diseases necessitate the exploration of new therapeutic candidates. In the present study, the lignan methylpiperitol was isolated after several chromatographic steps from Persea fulva L.â E. Koop (Lauraceae) and its leishmanicidal and trypanocidal activities were evaluated using inâ vitro and inâ silico approaches. The chemical structure of methylpiperitol was defined by NMR and MS spectral data analysis. The antiprotozoal activity of methylpiperitol was determined inâ vitro and indicated potency against trypomastigote forms of Trypanosoma cruzi (EC50 of 4.5±1.1â mM) and amastigote forms of Leishmania infantum (EC50 of 4.1±0.5â mM), with no mammalian cytotoxicity against NCTC cells (CC50>200â mM). Molecular docking studies were conducted using six T. cruzi and four Leishmania. The results indicate that for the molecular target hypoxanthine phosphoribosyl transferase in T. cruzi and piteridine reductase 1 of L. infatum, the methylpiperitol obtained better results than the crystallographic ligand. Therefore, the lignan methylpiperitol, isolated from P. fulva holds potential for the development of new prototypes for the treatment of Neglected Tropical Diseases, especially leishmaniasis.
Asunto(s)
Leishmania infantum , Lignanos , Simulación del Acoplamiento Molecular , Trypanosoma cruzi , Lignanos/farmacología , Lignanos/aislamiento & purificación , Lignanos/química , Trypanosoma cruzi/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/aislamiento & purificación , Animales , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/aislamiento & purificaciónRESUMEN
In Brazil, where Chagas disease is endemic, the most frequent form of transmission of the parasite is the oral route, associated with greater severity and worse response to benznidazole (BZ), the drug used in its treatment. This study aimed to evaluate the impact of gastrointestinal infection (GI) and BZ treatment on the parasitological and histopathological parameters in mice inoculated with a strain of T. cruzi II. Swiss mice were inoculated by GI and intraperitoneal (IP) routes with 2x106 culture-derived metacyclic trypomastigotes of the Y strain (TcII) of T. cruzi and were treated with BZ in the acute phase of the infection. Fresh blood examination, qPCR, histopathological and biochemical evaluations (enzymatic dosages and oxidative stress-OS) were performed. BZ treatment of uninfected animals caused changes in the liver, increased the activity of aspartate aminotransferase and alanine aminotransferase enzymes and OS, showing that the drug alone affects this organ. Inflammation and necrosis in the cardiac tissue were less intense and deaths occurred later in animals inoculated via the GI route than the animals inoculated via the IP route. BZ reduced the intensity of tissue lesions and avoided lethality in animals inoculated via the GI route, and decreased parasitemia and OS in those inoculated via both routes. Although BZ alone caused liver damage, it was less intense than that caused by both routes of inoculation. Infection with the Y strain of T. cruzi II via the GI route proved to be less virulent and pathogenic and responded better to treatment than the infection acquired via the IP route.
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Alanina Transaminasa , Aspartato Aminotransferasas , Enfermedad de Chagas , Corazón , Hígado , Nitroimidazoles , Parasitemia , Tripanocidas , Trypanosoma cruzi , Animales , Nitroimidazoles/uso terapéutico , Nitroimidazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Ratones , Tripanocidas/uso terapéutico , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Hígado/parasitología , Hígado/patología , Alanina Transaminasa/sangre , Corazón/parasitología , Corazón/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Miocardio/patología , Femenino , Enfermedades Gastrointestinales/parasitología , Enfermedades Gastrointestinales/tratamiento farmacológicoRESUMEN
American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6-7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients' treatment abandonment. Therefore, there is a need for new and better treatments. In this work, the molecular docking of nine hundred twenty-four FDA-approved drugs on three different sites of trypanothione reductase of T. cruzi (TcTR) was carried out to find potential trypanocidal agents. Finally, biological evaluations in vitro and in vivo were conducted with the selected FDA-approved drugs. Digoxin, alendronate, flucytosine, and dihydroergotamine showed better trypanocidal activity than the reference drugs benznidazole and nifurtimox in the in vitro evaluation against the trypomastigotes form. Further, these FDA-approved drugs were able to reduce 20-50% parasitemia in a short time in an in vivo model, although with less efficiency than benznidazole. Therefore, the results suggest a combined therapy of repurposed and canonical drugs against T. cruzi infection.
Asunto(s)
Enfermedad de Chagas , Simulación del Acoplamiento Molecular , NADH NADPH Oxidorreductasas , Tripanocidas , Trypanosoma cruzi , Tripanocidas/farmacología , Tripanocidas/química , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/química , NADH NADPH Oxidorreductasas/metabolismo , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Enfermedad de Chagas/tratamiento farmacológico , Animales , Humanos , United States Food and Drug Administration , Aprobación de Drogas , Evaluación Preclínica de Medicamentos , Estados Unidos , RatonesRESUMEN
Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.
[Box: see text].
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Aminopiridinas , Antiprotozoarios , Enfermedades Desatendidas , Trypanosoma brucei brucei , Trypanosoma cruzi , Enfermedades Desatendidas/tratamiento farmacológico , Humanos , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Aminopiridinas/química , Aminopiridinas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Leishmania/efectos de los fármacos , Desarrollo de Medicamentos , Pruebas de Sensibilidad Parasitaria , AnimalesAsunto(s)
Enfermedad de Chagas , Nifurtimox , Tripanocidas , Humanos , Nifurtimox/uso terapéutico , Nifurtimox/efectos adversos , Nifurtimox/administración & dosificación , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/diagnóstico , Tripanocidas/uso terapéutico , Tripanocidas/efectos adversos , Trypanosoma cruzi/efectos de los fármacos , Animales , Resultado del TratamientoRESUMEN
Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.
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Pirazoles , Tiadiazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , HumanosRESUMEN
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, 1H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.
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Lactonas , Especies Reactivas de Oxígeno , Sesquiterpenos , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/metabolismo , Sesquiterpenos/farmacología , Lactonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Tripanocidas/farmacología , Glutatión/metabolismo , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Proteínas Protozoarias/metabolismo , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Amida SintasasRESUMEN
Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 µM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.
Asunto(s)
Enfermedad de Chagas , G-Cuádruplex , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , G-Cuádruplex/efectos de los fármacos , Ligandos , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Parasitaria , Antiparasitarios/farmacología , Antiparasitarios/química , Antiparasitarios/síntesis químicaRESUMEN
There is an urgent need to develop new, safer, and more effective drugs against Chagas disease (CD) as well as related kinetoplastid diseases. Targeting and inhibiting the Trypanosoma cruzi proteasome has emerged as a promising therapeutic approach in this context. To expand the chemical space for this class of inhibitors, we performed virtual screening campaigns with emphasis on shape-based similarity and ADMET prioritization. We describe the ideation and application of robustly validated shape queries for these campaigns, which furnished 44 compounds for biological evaluation. Five hit compounds demonstrated in vitro antitrypanosomal activity by potential inhibition of T. cruzi proteasome and notable chemical diversities, particularly, LCQFTC11. Structural insights were achieved by homology modeling, sequence/structure alignment, proteasome-species comparison, docking, molecular dynamics, and MMGBSA binding affinity estimations. These methods confirmed key interactions as well as the stability of LCQFTC11 at the ß4/ß5 subunits' binding site of the T. cruzi proteasome, consistent with known inhibitors. Our results warrant future assay confirmation of our hit as a T. cruzi proteasome inhibitor. Importantly, we also shed light into dynamic details for a proteasome inhibition mechanism that shall be further investigated. We expect to contribute to the development of viable CD drug candidates through such a relevant approach.
Asunto(s)
Simulación del Acoplamiento Molecular , Complejo de la Endopetidasa Proteasomal , Inhibidores de Proteasoma , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Simulación de Dinámica Molecular , Tripanocidas/farmacología , Tripanocidas/química , Sitios de Unión , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Relación Estructura-Actividad , Unión ProteicaRESUMEN
Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.
Asunto(s)
Enfermedad de Chagas , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Tripanocidas , Trypanosoma cruzi , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Animales , Trypanosoma cruzi/efectos de los fármacos , Humanos , Desarrollo de MedicamentosRESUMEN
BACKGROUND: The current treatments for Chagas disease (CD) include benznidazole and nifurtimox, which have limited efficacy and cause numerous side effects. Triazoles are candidates for new CD treatments due to their ability to eliminate T. cruzi parasites by inhibiting ergosterol synthesis, thereby damaging the cell membranes of the parasite. METHODS: Eleven synthetic analogs of the kinase inhibitor SRPIN340 containing a triazole core (compounds 6A-6K) were screened in vitro against the Tulahuen strain transfected with ß-galactosidase, and their IC50, CC50, and selectivity indexes (SI) were calculated. Compounds with an SI > 50 were further evaluated in mice infected with the T. cruzi Y strain by rapid testing. RESULTS: Eight compounds were active in vitro with IC50 values ranging from 0.5-10.5 µg/mL. The most active compounds, 6E and 6H, had SI values of 125.2 and 69.6, respectively. These compounds also showed in vivo activity, leading to a reduction in parasitemia at doses of 10, 50, and 250 mg/kg/day. At doses of 50 and 250 mg/kg/day, parasitemia was significantly reduced compared to infected untreated animals, with no significant differences between the effects of 6E and 6H. CONCLUSIONS: This study identified two new promising compounds for CD chemotherapy and confirmed their activity against T. cruzi.
Asunto(s)
Enfermedad de Chagas , Triazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Animales , Triazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Ratones , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , TiazolesRESUMEN
In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.