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Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi

Published online by Cambridge University Press:  12 March 2019

M. R. Simões-Silva ,
J. S. De Araújo ,
R. B. Peres ,
P. B. Da Silva ,
M. M. Batista ,
L. D. De Azevedo ,
M. M. Bastos ,
M. T. Bahia ,
N. Boechat  and
M. N. C. Soeiro Open the ORCID record for M. N. C. Soeiro [Opens in a new window]
M. R. Simões-Silva
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
J. S. De Araújo
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
R. B. Peres
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
P. B. Da Silva
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
M. M. Batista
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
L. D. De Azevedo
Affiliation:
Laboratório de Síntese Orgânica, Instituto de Tecnologia em Fármacos – Farmanguinhos, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-900 Rio de Janeiro, Rio de Janeiro, Brazil Universidade Federal do Rio de Janeiro, Instituto de CiênciasBiomédicas – ICB, Centro de Ciências da Saúde – CCS, Bloco J, Ilha do Fundão, 21941-599 Rio de Janeiro, Rio de Janeiro, Brazil
M. M. Bastos
Affiliation:
Laboratório de Síntese Orgânica, Instituto de Tecnologia em Fármacos – Farmanguinhos, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-900 Rio de Janeiro, Rio de Janeiro, Brazil
M. T. Bahia
Affiliation:
Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário, Morro do Cruzeiro s/no, 35400-000 Ouro Preto, Minas Gerais, Brazil
N. Boechat
Affiliation:
Laboratório de Síntese Orgânica, Instituto de Tecnologia em Fármacos – Farmanguinhos, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-900 Rio de Janeiro, Rio de Janeiro, Brazil
M. N. C. Soeiro*
Affiliation:
Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Rio de Janeiro, Brazil
*
Author for correspondence: M. N. C. Soeiro, E-mail: soeiro@ioc.fiocruz.br
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Abstract

Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

Keywords

Chagas diseasedrug repurposingimatinibimatinib derivativesin vitro
Type
Research Article
Information
Parasitology , Volume 146 , Issue 8 , July 2019 , pp. 1006 - 1012
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Copyright
Copyright © Cambridge University Press 2019 

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