Ultrastructural analysis of edelfosine-treated trypomastigotes and amastigotes of Trypanosoma cruzi

Santa‐Rita, Ricardo M.; Barbosa, Helene Santos; Castro, Solange L. de

doi:10.1007/s00436-006-0250-8

Cited by 28 publications

(16 citation statements)

References 12 publications

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“…The present results show that DB1362 displays a trypanocidal effect against both bloodstream trypomastigotes and amastigotes localized within host cells in vitro, corroborating previous data that showed good dose-dependent activity of dicationic molecules against T. cruzi at noncytotoxic doses (5). The effect of DB1362 against bloodstream forms in the presence of mouse blood was reduced, possibly due to the association of the diamidine with serum components, as demonstrated with other drugs (22).…”

Section: Discussionsupporting

confidence: 91%

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

Silva

Batista

et al. 2008

Antimicrob Agents Chemother

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Aromatic diamidines are DNA minor groove-binding ligands that display excellent antimicrobial activity against fungi, bacteria, and protozoa. Due to the currently unsatisfactory chemotherapy for Chagas' disease and in view of our previous reports regarding the effect of diamidines and analogues against both in vitro and in vivo Trypanosoma cruzi infection, this study evaluated the effects of a diarylthiophene diamidine (DB1362) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas' disease. The data show the potent in vitro activity of DB1362 against both parasite forms that are relevant for mammalian infection at doses which do not exhibit cytotoxicity. Ultrastructural analysis and flow cytometry studies show striking alterations in the nuclei and mitochondria of the bloodstream parasites. In vivo studies were performed at two different drug concentrations (25 and 50 mg/kg/day) using a 2-day or a 10-day regimen. The best results were obtained when acutely infected mice were treated with two doses at the lower concentration, resulting in 100% survival, compared to the infected and untreated mice. Although it did not display higher efficacy than benznidazole, DB1362 reduced both cardiac parasitism and inflammation, and in addition, it protected against the cardiac alterations (determined by measurements) common in T. cruzi infection. These results support further investigation of diamidines and related compounds as potential agents against Chagas' disease.

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Section: Discussionsupporting

confidence: 91%

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

Silva

Batista

et al. 2008

Antimicrob Agents Chemother

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“…After treatment, the parasite suspension was incubated for 15 min at 37°C with 10 g/ml rhodamine 123 (Rh123). The samples were then immediately placed on ice and kept on ice until analysis, as reported previously (21). Data acquisition and analysis were performed with a FACSCalibur flow cytometer (Becton Dickinson, San Jose, CA) equipped with Cell Quest software (Joseph Trotter, Scripps Research Institute, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Cellular Effects of Reversed Amidines on Trypanosoma cruzi

Silva

Meuser

Souza

et al. 2007

Antimicrob Agents Chemother

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Aromatic diamidines represent a class of DNA minor groove-binding ligands that exhibit high levels of antiparasitic activity. Since the chemotherapy for Chagas' disease is still an unsolved problem and previous reports on diamidines and related analogues show that they have high levels of activity against Trypanosoma cruzi infection both in vitro and in vivo, our present aim was to evaluate the cellular effects in vitro of three reversed amidines (DB889, DB702, and DB786) and one diguanidine (DB711) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas ' disease. Our data show that the reversed amidines have higher levels of activity than the diguanidine, with the order of trypanocidal activities being as follows: DB889 > DB702 > DB786 > DB711. Transmission electron microscopy analysis showed that the reversed amidines induced many alterations in the nuclear morphology, swelling of the endoplasmic reticulum and Golgi structures, and consistent damage in the mitochondria and kinetoplasts of the parasites. Interestingly, in trypomastigotes treated with the reversed amidine DB889, multiple axoneme structures (flagellar microtubules) were noted. Flow cytometry analysis confirmed that the treated parasites presented an important loss of the mitochondrial membrane potential, as revealed by a decrease in rhodamine 123 fluorescence. Our results show that the reversed amidines have promising activities against the relevant mammalian forms of T. cruzi and display high trypanocidal effects at very low doses. This is especially the case for DB889, which merits further in vivo evaluation.Aromatic diamidines are DNA minor groove-binding ligands (MGBLs), which present striking broad-spectrum antimicrobial effects (28). Although this class of compounds displays significant in vitro and in vivo activities against fungi, amoeba, bacteria, and especially protozoan parasites, certain structures can show toxicity toward mammalian cells (23). In addition, aromatic diamidines in general lack oral bioavailability, which limits their use (28). To overcome these limitations, prodrugs such as the methamidoxime prodrug of furamidine (DB289), which is currently undergoing phase III clinical trials for the treatment of human African trypanosomiasis, have been developed (29). Trypanosoma cruzi is the etiological agent of Chagas' disease, a zoonosis considered a major public health problem in the developing countries of Central and South America (14). The disease is widespread in areas of endemicity in Latin America, and it has been estimated that the overall prevalence of human infection is about 17 million cases and that approximately 120 million people are at risk of contracting the infection (30). However, up to now there has been neither an effective vaccine nor a satisfactory treatment for the disease. Drug therapy depends mostly upon nitrofurans and nitroimidazoles, such as nifurtimox and benznidazole (4,26,27).Our previous studies revealed that furamidine and its Nphenyl-substituted analo...

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“…Multiple intracellular compartment damage has been reported with other active drugs against T. cruzi [35][36][37] . Mitochondrial swelling and the presence of concentric structures were frequently noticed in parasites treated with lysophospholipid analogues 38 and naphthoquinone derivatives 39 . Remarkable changes were also induced in the kinetoplast-mitochondrial system, microtubule, and reservosomes organization after treatment of T. cruzi with DNA-intercalating drugs and sterol biosynthesis inhibitors, leading to kinetoplast collapse and cell death 36,37,40 .…”

Section: Ultrastructural Analysis Of the Effect Of Had1 Inhibitor Agamentioning

confidence: 99%

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

Menezes

Calvet

Rodrigues

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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This work describes the antitrypanocidal activity of two hydroxamic acid derivatives containing o-ethoxy (HAD1) and p-ethoxy (HAD2) as substituent in the aromatic ring linked to the isoxazoline ring. HAD1 and HAD2 induced a significant reduction in the number of intracellular parasites and consequently showed activity on the multiplication of the parasite. Treatment of cardiomyocytes and macrophages with the compounds revealed no significant loss in cell viability. Ultrastructural alterations after treatment of cardiomyocytes or macrophages infected by Trypanosoma cruzi with the IC 50 value of HAD1 revealed alterations to amastigotes, showing initial damage seen as swelling of the kinetoplast. This gave a good indication of the ability of the drug to permeate through the host cell membrane as well as its selectivity to the parasite target. Both compounds HAD1 and 2 were able to reduce the cysteine peptidases and decrease the activity of metallopeptidases KeywordsChagas disease, hydroxamic acid derivatives, Trypanosoma cruzi History

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Ultrastructural analysis of edelfosine-treated trypomastigotes and amastigotes of Trypanosoma cruzi

Cited by 28 publications

References 12 publications

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

Cellular Effects of Reversed Amidines on Trypanosoma cruzi

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

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