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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

  • Cristina Fonseca-Berzal (a1), Cristiane França da Silva (a2), Denise da Gama Jaen Batista (a2), Gabriel Melo de Oliveira (a2), José Cumella (a3), Marcos Meuser Batista (a2), Raiza Brandão Peres (a2), Aline Silva da Gama Nefertiti (a2), José A. Escario (a1), Alicia Gómez-Barrio (a1), Vicente J. Arán (a3) and Maria de Nazaré Correia Soeiro (a2)...

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.

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Corresponding author

Author for correspondence: Cristina Fonseca-Berzal, E-mail: crfonseca@pdi.ucm.es

References

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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, 17031711.
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, 10881097.
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, 409415.
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, 389396.
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, 280285.
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.
Coura, JR and de Castro, SL (2002) A critical review on Chagas disease chemotherapy. Memórias do Instituto Oswaldo Cruz 97, 324.
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, 10951105.
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, 41914195.
Don, R and Ioset, JR (2014) Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. Parasitology 141, 140146.
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, 10491056.
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.
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, 295310.
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, 14691478.
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.
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, 12461259.
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].
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].
Francisco, AF, Jayawardhana, S, Lewis, MD, Taylor, MC and Kelly, JM (2017) Biological factors that impinge on Chagas disease drug development. Parasitology 144, 18711880.
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, 365371.
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, 16701682.
Martinez, F, Perna, E, Perrone, SV and Sosa Liprandi, A (2019) Chagas disease and heart failure: an expanding issue worldwide. European Cardiology 14, 8288.
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, 21042118.
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, 198206.
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, 124134.
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, 2940.
Patterson, S and Fairlamb, AH (2018) Current and future prospects of nitro-compounds as drugs for trypanosomiasis and leishmaniasis. Current Medicinal Chemistry 26, 44544475.
Patterson, S and Wyllie, S (2014) Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends in Parasitology 30, 289298.
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.
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, 1620.
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, 717.
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, 103107.
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, 233238.
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, 12891303.
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, 824838.
Shikanai-Yasuda, MA and Carvalho, NB (2012) Oral transmission of Chagas disease. Clinical Infectious Diseases 54, 845852.
Silva, LH and Nussenzweig, V (1953) Sobre uma cepa de Trypanosoma cruzi altamente virulenta para o camundongo branco. Folha Clínica e Biológica 20, 191207.
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, 4653.
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, 10551062.
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, 41514163.
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, 25832589.
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, 37203726.
Urbina, JA (2018) The long road towards a safe and effective treatment of chronic Chagas disease. The Lancet Infectious Diseases 18, 363365.
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, 214227.
World Health Organization (2015) Guidelines for the Treatment of Malaria, 3rd Edn. Geneva, Switzerland: World Health Organization.
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.
World Health Organization (2019) WHO Interim Guidelines for the Treatment of Gambiense Human African Trypanosomiasis. Geneva, Switzerland: World Health Organization.
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, 828833.
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, 433444.

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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

  • Cristina Fonseca-Berzal (a1), Cristiane França da Silva (a2), Denise da Gama Jaen Batista (a2), Gabriel Melo de Oliveira (a2), José Cumella (a3), Marcos Meuser Batista (a2), Raiza Brandão Peres (a2), Aline Silva da Gama Nefertiti (a2), José A. Escario (a1), Alicia Gómez-Barrio (a1), Vicente J. Arán (a3) and Maria de Nazaré Correia Soeiro (a2)...

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