Lack of correlation between in vitro susceptibility to Benznidazole and phylogenetic diversity of Trypanosoma cruzi, the agent of Chagas disease
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Benznidazole
Chagas Disease
Trypanocidal agent
Chagas disease is a so-called “neglected disease” and endemic to Latin America. Nifurtimox and benznidazole are drugs that have considerable efficacy in the treatment of the acute phase of the disease but cause many significant side effects. Furthermore, in the Chronic Phase its efficiency is reduced and their therapeutic effectiveness is dependent on the type of T. cruzi strain. For this reason, the present work aims to drive basic research towards the discovery of new chemical entities to treat Chagas disease. Differently substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines were synthesized by cyclocondensation of substituted flavones with ethylenediamine and tested as anti-Trypanosoma cruzi candidates. Epimastigotes of the Y strain from T. cruzi were used in this study and the number of parasites was determined in a Neubauer chamber. The most potent diaryldiazepine that reduced epimastigote proliferation exhibited an IC50 value of 0.25 μM, which is significantly more active than benznidazole.
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Chagas Disease
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Nifurtimox
Chagas Disease
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Chagas disease is caused by the parasite protozoan Trypanosoma cruzi (T. cruzi) and affects millions of people in over 21 countries in around the world. The main forms of treatment of this disease, benznidazole and nifurtimox, present low cure rates in the chronic phase and often have serious side effects. Herein, we describe the evaluation of the trypanocidal activity of arylsulfonamides. The arylsulfonamides were evaluated in vitro against the amastigote and trypomastigote forms of the parasite. An enantiomerically pure example of arylsulfonamide was also tested. The initial results suggest that the arylsulfonamides evaluated act as DNA binding agents. A moderate activity was monitored against the intracellular forms of T. cruzi, with the best compound exhibiting an IC50 value at 22 μM and a selectivity index of 120. However, the level of activity was not favorable for progressing towards in vivo studies for Chagas disease.
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Trypanocidal agent
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Trypanosoma cruzi (T. cruzi) is a parasitic protozoan transmitted to mammalian hosts by blood-sucking triatomine bugs. Infections by T. cruzi, known as Chagas' disease, pose a major public health problem in endemic countries in Central and South America. New chemotherapeutic agents are desired because of the lack of effective vaccines, undesirable side effects of anti-chagasic drugs in use such as nifurtimox and benznidazole, and the emergence of parasite resistance to these drugs. In the past two decades, novel advances and an improved understanding of the biology and biochemistry of T. cruzi have led to the identification of various targets for chemotherapy to treat Chagas' disease. In addition, many efforts have been undertaken to develop antichagasic agents, such as designed and synthesized compounds, natural products, and their derivatives, against a number of targets. Here, I mainly review recent studies on the antichagasic activities of natural products.
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Journal Article Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease Get access L.S. Filardi, L.S. Filardi Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil, C.P. 1743Department of Zoology, University of Minas Gerais, Belo Horizonte, Brazil Search for other works by this author on: Oxford Academic PubMed Google Scholar Z. Brener Z. Brener Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil, C.P. 1743Department of Zoology, University of Minas Gerais, Belo Horizonte, Brazil Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 81, Issue 5, September-October 1987, Pages 755–759, https://doi.org/10.1016/0035-9203(87)90020-4 Published: 01 October 1987 Article history Accepted: 10 December 1986 Published: 01 October 1987
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Abstract Chagas disease is a neglected tropical disease, endemic in Latin America and caused by the protozoan parasite Trypanosoma cruzi . Available treatments show low cure efficacy during the chronic phase of the disease and cause a series of side effects, reinforcing the need to develop new drugs against Chagas disease. In this work, we describe the optimization of a trypanocidal hit compound recently reported in phenotypic high‐throughput screening studies against Trypanosoma cruzi . A hit‐to‐lead process was initiated and a structure‐activity relationship against Trypanosoma cruzi was obtained after the synthesis and biological evaluation of 22 new benzenesulfonylpiperazine derivatives. From this structure‐activity relationship study, we identified three compounds with a promising predicted ADMET profile and potency comparable to the reference drug benznidazole, which are candidates for further development towards therapies for Chagas disease.
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The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations.Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions.The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies.The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death.These results suggest the studied combinations could be used in the treatment of Chagas disease.
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ABSTRACT Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi . The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi . This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC 50 s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.
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It was reported previously that 2-n-propylquinoline was active against the epimastigote form of Trypanosoma cruzi. The effects of oral treatments with benznidazole and 2-n-propylquinoline were evaluated in Balb/c mice infected with T. cruzi chronically. The reference drug and 2-n-propylquinoline were administered 60 days post-infection for 30 days at 25 mg/mL. At 35 days post-treatment, the serological tests (ELISA) of the 2-n- propylquinoline-treated mice were significantly different from the controls (p = 0.01) and the benznidazole-treated mice (p = 0.03), while this was not the case at 85 days post-treatment. These results are encouraging for continuing the investigation of other analogues of 2-n-propylquinoline in experimental chronic Chagas' disease.
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