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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: [email protected]
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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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References

Ashburn, TT and Thor, KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery 3, 673–683.Google Scholar
Azevedo, LD, Bastos, MM, Vasconcelos, FC, Hoelz, LVB, Silva Junior, FP, Dantas, RF, de Almeida, ACM, de Oliveira, AP, Gomes, LC, Maia, RC and Boechat, N (2017) Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia. Medicinal Chemistry Research 26, 2929–2941.Google Scholar
Batista, DG, Batista, MM, Oliveira, GM, Amaral, PB, Lannes-Vieira, J, Britto, CM, Junqueira, A, Lima, MM, Romanha, AJ, Sales, PA Jr, Stephens, CE, Boykin, DW and Soeiro, MNC (2010) Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas’ disease treatment. Antimicrobial Agents and Chemotherapy 54, 2940–2952.Google Scholar
Beckmann, S, Long, T, Scheld, C, Geyer, R, Caffrey, CR and Grevelding, CG (2014) Serum albumin and α-1 acid glycoprotein impedes the killing of Schistosoma mansoni by the tyrosine kinase inhibitor imatinib. International Journal for Parasitology: Drugs and Drug Resistance 4, 287–295.Google Scholar
Behera, R, Thomas, SM and Mensa-Wilmot, K (2014) New chemical scaffolds for human African trypanosomiasis lead discovery from a screen of tyrosine kinase inhibitor drugs. Antimicrobial Agents and Chemotherapy 58, 2202–2210.Google Scholar
Bermudez, J, Davies, C, Simonazzi, A, Real, JP and Palma, S (2016) Current drug therapy and pharmaceutical challenges for Chagas disease. Acta Tropica 156, 1–16.Google Scholar
Brener, Z and Chiari, E (1963) Variações morfológicas observadas em diferentes amostras de Trypanosoma cruzi. Revista do Instituto de Medicina Tropical de São Paulo 5, 220–244.Google Scholar
Buckner, FS, Verlinde, CL, La Flamme, AC and Van Voorhis, WC (1996) Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase. Antimicrobial Agents and Chemotherapy 40, 2592–2597.Google Scholar
Buro, C, Beckmann, S, Oliveira, KC, Dissous, C, Cailliau, K, Marhöfer, RJ, Selzer, PM, Verjovski-Almeida, S and Grevelding, CG (2014) Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects. PLoS Neglected Tropical Diseases 8, e2923.Google Scholar
Cha, Y, Erez, T, Reynolds, IJ, Kumar, D, Ross, J, Koytiger, G, Kusko, R, Zeskind, B, Risso, S, Kagan, E, Papapetropoulos, S, Grossman, I and Laifenfeld, D (2018) Pharma perspective on drug repurposing. British Journal of Pharmacology 175, 168–180. Epub 2017 May 18.Google Scholar
Chatelain, E (2016) Chagas disease research and development: Is there light at the end of the tunnel? Computational and Structural Biotechnology Journal 15, 98–103. eCollection 2017.Google Scholar
Cruz-Rico, J, Garrido-Acosta, O, Anguiano-Robledo, L, Rodríguez-Wong, U, Pérez-Cruz, E, Sánchez Navarrete, J, Ruiz-Pérez, NJ and Montes-Vera, MR (2013) Imatinib: farmacocinética. Revista del Hospital Juárez de México 80, 67–72.Google Scholar
De Rycker, M, Thomas, J, Riley, J, Brough, SJ, Miles, TJ and Gray, DW (2016) Identification of trypanocidal activity for known clinical compounds using a new Trypanosoma cruzi hit-discovery screening cascade. PLoS Neglected Tropical Diseases 10, e0004584.Google Scholar
De Souza, EM, Nefertiti, AS, Bailly, C, Lansiaux, A and Soeiro, MN (2010) Differential apoptosis-like cell death in amastigote and trypomastigote forms from Trypanosoma cruzi-infected heart cells in vitro. Cell Tissue Research 341, 173–180.Google Scholar
Devine, W, Thomas, SM, Erath, J, Bachovchin, KA, Lee, PJ, Leed, SE, Rodriguez, A, Sciotti, RJ, Mensa-Wilmot, K and Pollastri, MP (2017) Antiparasitic lead discovery: toward optimization of a chemotype with activity against multiple protozoan parasites. Medicinal Chemistry Letters 8, 350–354.Google Scholar
Dichiara, M, Marrazzo, A, Prezzavento, O, Collina, S, Rescifina, A and Amata, E (2017) Repurposing of human kinase inhibitors in neglected protozoan diseases. ChemMedChem 12, 1235–1253.Google Scholar
Diniz, LDF, Urbina, JA, de Andrade, IM, Mazzeti, AL, Martins, TA, Caldas, IS, Talvani, A, Ribeiro, I and Bahia, MT (2013) Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments. PLoS Neglected Tropical Diseases 7, e2367.Google Scholar
Engel, JC, Ang, KK, Chen, S, Arkin, MR, McKerrow, JH and Doyle, PS (2010) Image-based high-throughput drug screening targeting the intracellular stage of Trypanosoma cruzi, the agent of Chagas’ disease. Antimicrobial Agents and Chemotherapy 54, 3326–3334.Google Scholar
Fivelman, QL, Adagu, IS and Warhust, DC (2004) Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum. Antimicrobial Agents and Chemotherapy 48, 4097–4102.Google Scholar
Meirelles, MN, de Araujo-Jorge, TC, Miranda, CF, de Souza, W and Barbosa, HS (1986) Interaction of Trypanosoma cruzi with heart muscle cells: ultrastructural and cytochemical analysis of endocytic vacuole formation and effect upon myogenesis in vitro. European Journal of Cell Biology 41, 198–206.Google Scholar
Melo, TG, Tucci, AR, Nogueira, AR, de Meirelles, MN and Pereira, MC (2014) The involvement of FAK and Src in the invasion of cardiomyocytes by Trypanosoma cruzi. Experimental Parasitology 139, 49–57.Google Scholar
Moreno, BH, Cabanas, EG and Hitt, R (2010) Tyrosine kinase inhibitors in treating soft tissue sarcomas: sunitinib in non-gist sarcomas. Clinical Translational Oncology 12, 468–472.Google Scholar
Musumeci, F, Schenone, S, Grossi, G, Brullo, C and Sanna, M (2015) Analogs, formulations and derivatives of imatinib: a patent review. Expert Opinion on Therapeutic Patents 25, 1411–1421.Google Scholar
Nwaka, S and Hudson, A (2006) Innovative lead discovery strategies for tropical diseases. Nature Reviews Drug Discovery 5, 941–955.Google Scholar
O'Connell, EM, Bennuru, S, Steel, C, Dolan, MA and Nutman, TB (2015) Targeting filarial Abl-like kinases: orally available, food and drug administration-approved tyrosine kinase inhibitors are microfilaricidal and macrofilaricidal. Journal of Infectious Diseases 212, 684–693.Google Scholar
Papadopoulou, MV, Bloomer, WD, Rosenzweig, HS, O'Shea, IP, Wilkinson, SR, Kaiser, M, Chatelain, E and Ioset, JR (2015) Discovery of potent nitrotriazole-based antitrypanosomal agents: in vitro and in vivo evaluation. Bioorganic & Medicinal Chemistry 23, 6467–6476.Google Scholar
Pathak, V, Colah, R and Ghosh, K (2015) Tyrosine kinase inhibitors: new class of antimalarials on the horizon? Blood Cells, Molecules and Diseases 55, 119–126.Google Scholar
Prata, A (2001) Clinical and epidemiological aspects of Chagas disease. The Lancet Infectious Diseases 1, 92–100.Google Scholar
Rassi, AJ, Rassi, A and Marin-Neto, A (2010) Chagas disease. The Lancet 375, 1388–1402.Google Scholar
Rix, U, Hantschel, O, Dürnberger, G, Remsing Rix, LL, Planyavsky, M, Fernbach, NV, Kaupe, I, Bennett, KL, Valent, P, Colinge, J, Köcher, T and Superti-Furga, G (2007) Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood Journal 110, 4055–4063. Epub 2007 Aug 24.Google Scholar
Romanha, AJ, De Castro, SL, Soeiro, MNC, Lannes-Vieira, J, Ribeiro, I, Talvani, A, Bourdin, B, Blum, B, Olivieri, B, Zani, C, Spadafora, C, Chiari, E, Chatelain, E, Chaves, G, Calzada, JE, Bustamante, JM, Freitas-Junior, LH, Romero, LI, Bahia, MT, Lotrowska, M, Soares, M, Andrade, SG, Armstrong, T, Degrave, W and Andrade, ZA (2010) In vitro and in vivo experimental models for drug screening and development for Chagas disease. Memórias do Instituto Oswaldo Cruz 105, 233–238.Google Scholar
Santos, CC, Lionel, JR, Peres, RB, Batista, MM, da Silva, PB, de Oliveira, GM, da Silva, CF, Batista, DGJ, Souza, SMO, Andrade, CH, Neves, BJ, Braga, RC, Patrick, DA, Bakunova, SM, Tidwell, RR and Soeiro, MNC (2018) In vitro, in silico, and in vivo analyses of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 62, pii: e02205–17.Google Scholar
Simões-Silva, MR, Nefertiti, ASG, De Araújo, JS, Batista, MM, Da Silva, PB, Bahia, MT, Menna-Barreto, RS, Pavão, BP, Green, J, Farahat, AA, Kumar, A, Boykin, DW and Soeiro, MNC (2016) Phenotypic screening in vitro of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 60, 4701–4707.Google Scholar
Soeiro, MdeN, de Souza, EM, da Silva, CF, da Batista, DG, Batista, MM, Pavão, BP, Araújo, JS, Aiub, CA, da Silva, PB, Lionel, J, Britto, C, Kim, K, Sulikowski, G, Hargrove, TY, Waterman, MR and Lepesheva, GI (2013) In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 57, 4151–4163. Epub 2013 Jun 17.Google Scholar
Sun, W, Sanderson, PE and Zheng, W (2016) Drug combination therapy increases successful drug repositioning. Drug Discovery Today 21, 1189–1195.Google Scholar
Timm, BL, Da Silva, PB, Batista, MM, Farahat, AA, Kumar, A, Boykin, DW and Soeiro, MNC (2014) In vitro investigation of the efficacy of novel diamidines against Trypanosoma cruzi. Parasitology 141, 1272–1276.Google Scholar
Wetzel, DM, McMahon-Pratt, D and Koleske, AJ (2012) The Abl and Arg kinases mediate distinct modes of phagocytosis and are required for maximal Leishmania infection. Molecular and Cellular Biology 32, 3176–3186.Google Scholar
World Health Organization (2015) Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Weekly Epidemiological Records 90, 33–43.Google Scholar
Zingales, B, Miles, MA, Campbell, DA, Tibayrenc, M, Macedo, AM, Teixeira, MM, Schijman, AG, Llewellyn, MS, Lages-Silva, E, Machado, CR, Andrade, SG and Sturm, NR (2012) The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. Infection, Genetics and Evolution 12, 240–253.Google Scholar