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Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in...

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Autores principales: de Castro, Solange L., Batista, Denise G. J., Batista, Marcos M., Batista, Wanderson, Daliry, Anissa, de Souza, Elen M., Menna-Barreto, Rubem F. S., Oliveira, Gabriel M., Salomão, Kelly, Silva, Cristiane F., Silva, Patricia B., Soeiro, Maria de Nazaré C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE-Hindawi Access to Research 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195292/
https://www.ncbi.nlm.nih.gov/pubmed/22091400
http://dx.doi.org/10.4061/2011/306928
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author de Castro, Solange L.
Batista, Denise G. J.
Batista, Marcos M.
Batista, Wanderson
Daliry, Anissa
de Souza, Elen M.
Menna-Barreto, Rubem F. S.
Oliveira, Gabriel M.
Salomão, Kelly
Silva, Cristiane F.
Silva, Patricia B.
Soeiro, Maria de Nazaré C.
author_facet de Castro, Solange L.
Batista, Denise G. J.
Batista, Marcos M.
Batista, Wanderson
Daliry, Anissa
de Souza, Elen M.
Menna-Barreto, Rubem F. S.
Oliveira, Gabriel M.
Salomão, Kelly
Silva, Cristiane F.
Silva, Patricia B.
Soeiro, Maria de Nazaré C.
author_sort de Castro, Solange L.
collection PubMed
description Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.
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spelling pubmed-31952922011-11-16 Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones de Castro, Solange L. Batista, Denise G. J. Batista, Marcos M. Batista, Wanderson Daliry, Anissa de Souza, Elen M. Menna-Barreto, Rubem F. S. Oliveira, Gabriel M. Salomão, Kelly Silva, Cristiane F. Silva, Patricia B. Soeiro, Maria de Nazaré C. Mol Biol Int Review Article Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi. SAGE-Hindawi Access to Research 2011 2011-06-30 /pmc/articles/PMC3195292/ /pubmed/22091400 http://dx.doi.org/10.4061/2011/306928 Text en Copyright © 2011 Solange L. de Castro et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Article
de Castro, Solange L.
Batista, Denise G. J.
Batista, Marcos M.
Batista, Wanderson
Daliry, Anissa
de Souza, Elen M.
Menna-Barreto, Rubem F. S.
Oliveira, Gabriel M.
Salomão, Kelly
Silva, Cristiane F.
Silva, Patricia B.
Soeiro, Maria de Nazaré C.
Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title_full Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title_fullStr Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title_full_unstemmed Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title_short Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones
title_sort experimental chemotherapy for chagas disease: a morphological, biochemical, and proteomic overview of potential trypanosoma cruzi targets of amidines derivatives and naphthoquinones
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195292/
https://www.ncbi.nlm.nih.gov/pubmed/22091400
http://dx.doi.org/10.4061/2011/306928
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