Screening of Potential anti-Trypanosoma cruzi Candidates: In Vitro and In Vivo Studies

ABSTRACT Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K i values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.

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Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Parasitology ◽

10.1017/s0031182020000955 ◽

2020 ◽

Vol 147 (11) ◽

pp. 1216-1228

Author(s):

Cristina Fonseca-Berzal ◽

Cristiane França da Silva ◽

Denise da Gama Jaen Batista ◽

Gabriel Melo de Oliveira ◽

José Cumella ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Positive Impact ◽

Cardiac Cells ◽

In Vivo Studies ◽

Drug Resistant ◽

Activity Profile ◽

Reference Drug ◽

Novel Drugs

AbstractIn previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

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Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

Molecules ◽

10.3390/molecules22061015 ◽

2017 ◽

Vol 22 (6) ◽

pp. 1015 ◽

Cited By ~ 14

Author(s):

Isidro Palos ◽

Edgar E. Lara-Ramirez ◽

Julio Cesar Lopez-Cedillo ◽

Carlos Garcia-Perez ◽

Muhammad Kashif ◽

...

Keyword(s):

Virtual Screening ◽

Trypanosoma Cruzi ◽

In Vivo Studies ◽

Screening In Vitro ◽

Cruzain Inhibitors

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Promising Efficacy of Benznidazole Nanoparticles in Acute Trypanosoma cruzi Murine Model: In-Vitro and In-Vivo Studies

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.15-0889 ◽

2016 ◽

Vol 95 (2) ◽

pp. 388-393 ◽

Cited By ~ 15

Author(s):

María L. Scalise ◽

Mónica I. Esteva ◽

Marcela S. Rial ◽

Laura E. Fichera ◽

Eva C. Arrúa ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Murine Model ◽

In Vivo Studies

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In Vitro and In Vivo Studies of the Trypanocidal Activity of Four Terpenoid Derivatives against Trypanosoma cruzi

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2012.11-0471 ◽

2012 ◽

Vol 87 (3) ◽

pp. 481-488 ◽

Cited By ~ 12

Author(s):

Inmaculada Ramírez-Macías ◽

Manuel Sánchez-Moreno ◽

Enrique Alvarez-Manzaneda ◽

Ramón Gutierrez-Sánchez ◽

María José Rosales ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

In Vivo Studies ◽

Trypanocidal Activity

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00038-08 ◽

2008 ◽

Vol 52 (9) ◽

pp. 3307-3314 ◽

Cited By ~ 43

Author(s):

Cristiane França da Silva ◽

Marcos Meuser Batista ◽

Denise da Gama Jaen Batista ◽

Elen Mello de Souza ◽

Patrícia Bernardino da Silva ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

In Vivo Studies ◽

Groove Binding ◽

Dna Minor Groove ◽

Drug Concentrations ◽

Mammalian Infection ◽

Related Compounds

ABSTRACT 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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