Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-25T18:25:28.528Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  12 June 2020

Cristina Fonseca-Berzal Open the ORCID record for Cristina Fonseca-Berzal [Opens in a new window] ,
Cristiane França da Silva ,
Denise da Gama Jaen Batista ,
Gabriel Melo de Oliveira ,
José Cumella ,
Marcos Meuser Batista ,
Raiza Brandão Peres ,
Aline Silva da Gama Nefertiti ,
José A. Escario  and
Alicia Gómez-Barrio
...Show all authors
Cristina Fonseca-Berzal*
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Cristiane França da Silva
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Denise da Gama Jaen Batista
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Gabriel Melo de Oliveira
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
José Cumella
Affiliation:
Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain
Marcos Meuser Batista
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Raiza Brandão Peres
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Aline Silva da Gama Nefertiti
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
José A. Escario
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Alicia Gómez-Barrio
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Vicente J. Arán
Affiliation:
Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain
Maria de Nazaré Correia Soeiro
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
*
Author for correspondence: Cristina Fonseca-Berzal, E-mail: crfonseca@pdi.ucm.es
Get access Rights & Permissions [Opens in a new window]

Abstract

In 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.

Keywords

5-nitroindazoleChagas diseasechemotherapyin vitroin vivo
Type
Research Article
Information
Parasitology , Volume 147 , Issue 11 , September 2020 , pp. 1216 - 1228
Check for updates
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Almeida, TC, Ribeiro, LHG, Ferreira dos Santos, LB, da Silva, CM, Branquinho, RT, de Lana, M, Gadelha, FR and de Fátima, Â (2018) Synthesis, in vitro and in vivo anti-Trypanosoma cruzi and toxicological activities of nitroaromatic Schiff bases. Biomedicine and Pharmacotherapy 108, 1703–1711.CrossRefGoogle Scholar
Arias, DG, Herrera, FE, Garay, AS, Rodrigues, D, Forastieri, PS, Luna, LE, Bürgi, MDLM, Prieto, C, Iglesias, AA, Cravero, RM and Guerrero, SA (2018) Rational design of nitrofuran derivatives: synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase. European Journal of Medicinal Chemistry 125, 1088–1097.CrossRefGoogle Scholar
Botelho, AFM, Joviano-Santos, JV, Santos-Miranda, A, Menezes-Filho, JER, Soto-Blanco, B, Cruz, JS, Guatimosim, C and Melo, MM (2019) Non-invasive ECG recording and QT interval correction assessment in anesthetized rats and mice. Pesquisa Veterinária Brasileria 39, 409–415.CrossRefGoogle Scholar
Brener, Z (1962) Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Revista do Instituto de Medicina Tropical de São Paulo 4, 389–396.Google ScholarPubMed
Campos, JDS, Hoppe, LY, Duque, TLA, de Castro, SL and Oliveira, GM (2016) Use of noninvasive parameters to evaluate Swiss Webster mice during Trypanosoma cruzi experimental acute infection. Journal of Parasitology 102, 280–285.CrossRefGoogle ScholarPubMed
Chaves e Mello, FV, Quaresma, BMCS, Pitombeira, MCR, de Brito, MA, Farias, PP, de Castro, SL, Salomão, K, de Carvalho, AS, de Paula, JIO, Nascimento, SB, Cupello, MP, Paes, MC, Boechat, N and Felzenszwalb, I (2020) Novel nitroimidazole derivatives evaluated for their trypanocidal, cytotoxic, and genotoxic activities. European Journal of Medicinal Chemistry 186, 111887.CrossRefGoogle Scholar
Coura, JR and de Castro, SL (2002) A critical review on Chagas disease chemotherapy. Memórias do Instituto Oswaldo Cruz 97, 3–24.CrossRefGoogle Scholar
da Silva, CF, Batista, DGJ, de Araújo, JS, Cunha-Júnior, EF, Stephens, CE, Banerjee, M, Farahat, AA, Akay, S, Fisher, MK, Boykin, DW and Soeiro, MNC (2017) Phenotypic evaluation and in silico aDMeT properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection. Drug Design, Development and Therapy 11, 1095–1105.CrossRefGoogle ScholarPubMed
de Araújo, JS, da Silva, CF, Batista, DGJ, da Silva, PB, Meuser, MB, Aiub, CAF, da Silva, MFV, Araújo-Lima, CF, Banerjee, M, Farahat, AA, Stephens, CE, Kumar, A, Boykin, DW and Soeiro, MNC (2014) The biological activity of novel arylimidamides against Trypanosoma cruzi: in vitro and in vivo studies. Antimicrobial Agents and Chemotherapy 58, 4191–4195.CrossRefGoogle ScholarPubMed
Don, R and Ioset, JR (2014) Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. Parasitology 141, 140–146.CrossRefGoogle ScholarPubMed
Fonseca-Berzal, C, Escario, JA, Arán, VJ and Gómez-Barrio, A (2014). Further insights into biological evaluation of new anti-Trypanosoma cruzi 5-nitroindazoles. Parasitology Research 113, 1049–1056.CrossRefGoogle ScholarPubMed
Fonseca-Berzal, C, da Silva, PB, da Silva, CF, Vasconcelos, M, Batista, MM, Escario, JA, Arán, VJ, Gómez-Barrio, A and Soeiro, MNC (2015) Exploring the potential activity spectrum of two 5-nitroindazolinone prototypes on different Trypanosoma cruzi strains. Parasitology Open 1, e1.CrossRefGoogle Scholar
Fonseca-Berzal, C, Ibáñez-Escribano, A, Reviriego, F, Cumella, J, Morales, P, Jagerovic, N, Nogal-Ruiz, JJ, Escario, JA, da Silva, PB, Soeiro, MNC, Gómez-Barrio, A and Arán, VJ (2016 a) Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles. European Journal of Medicinal Chemistry 115, 295–310.CrossRefGoogle ScholarPubMed
Fonseca-Berzal, C, da Silva, CF, Menna-Barreto, RFS, Batista, MM, Escario, JA, Arán, VJ, Gómez-Barrio, A and Soeiro, MNC (2016 b) Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes. Parasitology 143, 1469–1478.CrossRefGoogle ScholarPubMed
Fonseca-Berzal, C, da Silva, CF, Batista, MM, Guedes-da-Silva, FH, Vasconcelos, M, Demarque, KC, Escario, JA, Arán, VJ, Soeiro, MNC and Gómez-Barrio, A (2017) Activity of 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one on Trypanosoma cruzi bloodstream trypomastigotes (Y strain): in vitro and in vivo studies. Proceedings 1, 655.CrossRefGoogle Scholar
Fonseca-Berzal, C, Ibáñez-Escribano, A, Vela, N, Cumella, J, Nogal-Ruiz, JJ, Escario, JA, da Silva, PB, Batista, MM, Soeiro, MNC, Sifontes-Rodríguez, S, Meneses-Marcel, A, Gómez-Barrio, A and Arán, VJ (2018) Antichagasic, leishmanicidal, and trichomonacidal activity of 2-benzyl-5-nitroindazole-derived amines. ChemMedChem 13, 1246–1259.CrossRefGoogle ScholarPubMed
Fonseca-Berzal, C, da Silva, CF, Batista, MM, Guedes-da-Silva, FH, Vasconcelos, M, Demarque, KC, Escario, JA, Arán, VJ, Gómez-Barrio, A and Soeiro, MNC (2019 a) Exploring the effectiveness in vivo of compound 1-(3-aminopropyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (hydrochloride) against Trypanosoma cruzi. XXI Congreso de la Sociedad Española de Parasitología, Pontevedra, Spain, Abstract book, 296 [97].Google Scholar
Fonseca-Berzal, C, da Silva, CF, Batista, MM, Guedes-da-Silva, FH, Vasconcelos, M, Demarque, KC, Escario, JA, Arán, VJ, Gómez-Barrio, A and Soeiro, MNC (2019 b) In vivo assessment of the activity of compound 2-benzyl-1-(3-methylaminopropyl)-5-nitro-1,2-dihydro-3H-indazol-3-one (hydrochloride) against Trypanosoma cruzi. XXI Congreso de la Sociedad Española de Parasitología, Pontevedra, Spain, Abstract book, 297 [98].Google Scholar
Francisco, AF, Jayawardhana, S, Lewis, MD, Taylor, MC and Kelly, JM (2017) Biological factors that impinge on Chagas disease drug development. Parasitology 144, 1871–1880.CrossRefGoogle ScholarPubMed
Guedes-da-Silva, FH, Batista, DGJ, da Silva, CF, Pavão, BP, Batista, MM, Moreira, OC, Souza, LRQ, Britto, C, Rachakonda, G, Villalta, F, Lepesheva, GI and Soeiro, MNC (2019) Successful aspects of the coadministration of sterol 14α-demethylase inhibitor VFV and benznidazole in experimental mouse models of Chagas disease caused by the drug-resistant strain of Trypanosoma cruzi. ACS Infectious Diseases 5, 365–371.CrossRefGoogle ScholarPubMed
Leite, DI, Fontes, FV, Bastos, MM, Hoelz, LVB, Bianco, MCAD, de Oliveira, AP, da Silva, PB, da Silva, CF, Batista, DGJB, Nefertiti, ASG, Peres, RB, Villar, JDF, Soeiro, MNC and Boechat, N (2018) New 12,3-triazole-based analogues of benznidazole for use against Trypanosoma cruzi infection: in vitro and in vivo evaluations. Chemical Biology and Drug Design 92, 1670–1682.CrossRefGoogle Scholar
Martinez, F, Perna, E, Perrone, SV and Sosa Liprandi, A (2019) Chagas disease and heart failure: an expanding issue worldwide. European Cardiology 14, 82–88.CrossRefGoogle ScholarPubMed
Martín-Escolano, R, Aguilera-Venegas, B, Marín, C, Martín-Montes, A, Martín-Escolano, J, Medina-Carmona, E, Arán, VJ and Sánchez-Moreno, M (2018) Synthesis and biological in vitro and in vivo evaluation of 2-(5-nitroindazol-1-yl) ethylamines and related compounds as potential therapeutic alternatives for Chagas disease. ChemMedChem 13, 2104–2118.CrossRefGoogle ScholarPubMed
Meirelles, MN, de Araújo-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 ScholarPubMed
Muro, B, Reviriego, F, Navarro, P, Marín, C, Ramírez-Macías, I, Rosales, MJ, Sánchez-Moreno, M and Arán, VJ (2014) New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles. European Journal of Medicinal Chemistry 74, 124–134.CrossRefGoogle ScholarPubMed
Palace-Berl, F, Pasqualoto, KFM, Zingales, B, Moraes, CB, Bury, M, Franco, CH, da Silva Neto, AL, Murayama, JS, Nunes, SL, Silva, MS and Tavares, LC (2018) Investigating the structure-activity relationships of N’-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds. European Journal of Medicinal Chemistry 144, 29–40.CrossRefGoogle ScholarPubMed
Patterson, S and Fairlamb, AH (2018) Current and future prospects of nitro-compounds as drugs for trypanosomiasis and leishmaniasis. Current Medicinal Chemistry 26, 4454–4475.CrossRefGoogle Scholar
Patterson, S and Wyllie, S (2014) Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends in Parasitology 30, 289–298.CrossRefGoogle ScholarPubMed
Petravicius, PO, Costa-Martins, AG, Silva, MN, Reis-Cunha, JL, Bartholomeu, DC, Teixeira, MMG and Zingales, B (2019) Mapping benznidazole resistance in trypanosomatids and exploring evolutionary histories of nitroreductases and ABCG transporter protein sequences. Acta Tropica 200, 105161.CrossRefGoogle ScholarPubMed
Pinazo, MJ and Gascón, J (2015) The importance of the multidisciplinary approach to deal with the new epidemiological scenario of Chagas disease (global health). Acta Tropica 151, 16–20.CrossRefGoogle Scholar
Ribeiro, V, Dias, N, Paiva, T, Hagström-Bex, L, Nitz, N, Pratesi, R and Hecht, M (2020) Current trends in the pharmacological management of Chagas disease. International Journal for Parasitology: Drugs and Drug Resistance 12, 7–17.Google ScholarPubMed
Rolón, M, Vega, C, Escario, JA and Gómez-Barrio, A (2006) Development of resazurin microtiter assay for drug sensibility testing of Trypanosoma cruzi epimastigotes. Parasitology Research 99, 103–107.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Sales Junior, PA, Molina, I, Murta, SMF, Sanchez-Montalvá, A, Salvador, F, Corrêa-Oliveira, R and Carneiro, CM (2017) Experimental and clinical treatment of Chagas disease: a review. The American Journal of Tropical Medicine and Hygiene 97, 1289–1303.CrossRefGoogle ScholarPubMed
Scarim, CB, Jornada, DH, Chelucci, RC, de Almeida, L, dos Santos, JL and Chin, CM (2018) Current advances in drug discovery for Chagas disease. European Journal of Medicinal Chemistry 155, 824–838.CrossRefGoogle ScholarPubMed
Shikanai-Yasuda, MA and Carvalho, NB (2012) Oral transmission of Chagas disease. Clinical Infectious Diseases 54, 845–852.CrossRefGoogle ScholarPubMed
Silva, LH and Nussenzweig, V (1953) Sobre uma cepa de Trypanosoma cruzi altamente virulenta para o camundongo branco. Folha Clínica e Biológica 20, 191–207.Google Scholar
Simões-Silva, MR, de Araújo, JS, Oliveira, GM, Demarque, KC, Peres, RB, d'Almeida-Melo, I, Batista, DGJ, da Silva, CF, Cardoso-Santos, C, da Silva, PB, Batista, MM, Bahia, MT and Soeiro, MNC (2017) Drug repurposing strategy against Trypanosoma cruzi infection: in vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy. Biochemical Pharmacology 145, 46–53.CrossRefGoogle ScholarPubMed
Simões-Silva, MR, Peres, RB, Britto, C, Cascabulho, CM, Oliveira, GM, da Gama, AN, da Silva, CF, da Costa, KL, Araújo, PF, Campos, JDS, Batista, MM, Demarque, KC, Moreira, OC and Soeiro, MNC (2019) Impact of levamisole in co-administration with benznidazole on experimental Chagas disease. Parasitology 146, 1055–1062.CrossRefGoogle Scholar
Soeiro, MNC, de Souza, EM, da Silva, CF, Batista, DGJ, Batista, MM, Pavão, BP, de Araújo, JS, Fortes 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.CrossRefGoogle Scholar
Thompson, AM, Blaser, A, Palmer, BD, Anderson, RF, Shinde, SS, Launay, D, Chatelain, E, Maes, L, Franzblau, SG, Wan, B, Wang, Y, Ma, Z and Denny, WA (2017) 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases. Bioorganic and Medicinal Chemistry Letters 27, 2583–2589.CrossRefGoogle Scholar
Timm, BL, da Silva, PB, Batista, MM, da Silva, FHG, da Silva, CF, Tidwell, RR, Patrick, DA, Jones, SK, Bakunov, SA, Bakunova, SM and Soeiro, MNC (2014) In vitro and in vivo biological effects of novel arylimidamide derivatives against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 58, 3720–3726.CrossRefGoogle ScholarPubMed
Urbina, JA (2018) The long road towards a safe and effective treatment of chronic Chagas disease. The Lancet Infectious Diseases 18, 363–365.CrossRefGoogle Scholar
Vega, MC, Rolón, M, Montero-Torres, A, Fonseca-Berzal, C, Escario, JA, Gómez-Barrio, A, Gálvez, J, Marrero-Ponce, Y and Arán, VJ (2012) Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug. European Journal of Medicinal Chemistry 58, 214–227.CrossRefGoogle ScholarPubMed
World Health Organization (2015) Guidelines for the Treatment of Malaria, 3rd Edn. Geneva, Switzerland: World Health Organization.Google Scholar
World Health Organization (2017) Integrating Neglected Tropical Diseases into Global Health and Development. Fourth WHO report on neglected tropical diseases. Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland.Google Scholar
World Health Organization (2019) WHO Interim Guidelines for the Treatment of Gambiense Human African Trypanosomiasis. Geneva, Switzerland: World Health Organization.Google Scholar
Zingales, B, Miles, MA, Moraes, CB, Luquetti, A, Guhl, F, Schijman, AG and Ribeiro, I (2014) Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity. Memórias do Instituto Oswaldo Cruz 109, 828–833.CrossRefGoogle ScholarPubMed
Zingales, B, Araujo, RGA, Moreno, M, Franco, J, Aguiar, PHN, Nunes, SL, Silva, MN, Ienne, S, Machado, CR and Brandão, A (2015) A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole. Memórias do Instituto Oswaldo Cruz 110, 433–444.CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Fonseca-Berzal Supplementary Materials

Fonseca-Berzal Supplementary Materials

Download Fonseca-Berzal Supplementary Materials(PDF)
PDF 283 KB