Nitroindazolinone derivatives: assessing the impact of the nitro group location on the activity against Trypanosoma cruzi
- 1Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid, Spain
- 2Laboratório de Biologia Celular (LBC), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil
- 3Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
Abstract
In the last decades, different 5-nitroindazole-based compounds have been synthesized and proposed as potential agents for treating the infection caused by Trypanosoma cruzi, i.e. Chagas disease. In previous works, the 1,2-disubstituted 5-nitroindazolinone system has been identified as a promising scaffold to design compounds, among which derivatives with a benzyl moiety at N-2 stand out. Now, we have synthesized 4-, 6- and 7-nitroindazolin-3-ones (19–24), analogues of the previously studied 2-benzyl-1-methyl-5-nitroindazolinone (1) and 2-benzyl-5-nitro-1-propylindazolinone (2), to explore the impact of the nitro group position on their trypanocidal activity. These 8 nitro derivatives were in silico predicted to have good oral bioavailability and no toxicity risks. In vitro assays over bloodstream trypomastigotes (Y strain, DTU TcII) showed an improvement in the lytic profile of 2-benzyl-1-propyl derivatives, when the NO2 group is moved to position 6 of the indazole ring: EC50 = 34.55 µM (23) versus EC50 > 50 µM (2, 22 and 24). Regarding the assays on amastigotes (Tulahuen strain, DTU TcVI), 4-, 6- and 7-nitroindazoles did not display better activity (EC50 from 3.82 to > 20 µM) than 5-nitroindazoles, with EC50 = 2.34 (1) and 3.03 µM (2). The lack of cytotoxicity over cardiac (CC50 > 200 µM) and L929 cells (CC50 > 170 µM) supports selective action, particularly of 5-nitroindazolinones towards intracellular forms: SI > 85.47 (1) and 56.53 (2). Altogether, data indicate that the anti-T. cruzi activity of 4-, 6- and 7-nitroindazolinones is not better than that of 1 and 2, not presenting significant advantages over these two 5-nitroindazolinones.
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BibTeX
@article{fonsecaberzal2026nitroindazolinone,
title = {{Nitroindazolinone derivatives: assessing the impact of the nitro group location on the activity against Trypanosoma cruzi}},
author = {Cristina Fonseca-Berzal and Cristiane França da Silva and Patrícia Bernardino da Silva and Marcos Meuser Batista and Alicia Gómez-Barrio and Nerea Vela and Vicente J. Arán and Maria de Nazaré Correia Soeiro},
journal = {Parasitology},
year = {2026},
month = aug,
doi = {10.1017/s0031182026102613},
url = {https://doi.org/10.1017/s0031182026102613},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Nitroindazolinone derivatives: assessing the impact of the nitro group location on the activity against Trypanosoma cruzi
AU - Cristina Fonseca-Berzal
AU - Cristiane França da Silva
AU - Patrícia Bernardino da Silva
AU - Marcos Meuser Batista
AU - Alicia Gómez-Barrio
AU - Nerea Vela
AU - Vicente J. Arán
AU - Maria de Nazaré Correia Soeiro
PY - 2026
DA - 2026/08/03
JO - Parasitology
DO - 10.1017/s0031182026102613
UR - https://doi.org/10.1017/s0031182026102613
AB - In the last decades, different 5-nitroindazole-based compounds have been synthesized and proposed as potential agents for treating the infection caused by Trypanosoma cruzi, i.e. Chagas disease. In previous works, the 1,2-disubstituted 5-nitroindazolinone system has been identified as a promising scaffold to design compounds, among which derivatives with a benzyl moiety at N-2 stand out. Now, we have synthesized 4-, 6- and 7-nitroindazolin-3-ones (19–24), analogues of the previously studied 2-benzyl-1-methyl-5-nitroindazolinone (1) and 2-benzyl-5-nitro-1-propylindazolinone (2), to explore the impact of the nitro group position on their trypanocidal activity. These 8 nitro derivatives were in silico predicted to have good oral bioavailability and no toxicity risks. In vitro assays over bloodstream trypomastigotes (Y strain, DTU TcII) showed an improvement in the lytic profile of 2-benzyl-1-propyl derivatives, when the NO2 group is moved to position 6 of the indazole ring: EC50 = 34.55 µM (23) versus EC50 > 50 µM (2, 22 and 24). Regarding the assays on amastigotes (Tulahuen strain, DTU TcVI), 4-, 6- and 7-nitroindazoles did not display better activity (EC50 from 3.82 to > 20 µM) than 5-nitroindazoles, with EC50 = 2.34 (1) and 3.03 µM (2). The lack of cytotoxicity over cardiac (CC50 > 200 µM) and L929 cells (CC50 > 170 µM) supports selective action, particularly of 5-nitroindazolinones towards intracellular forms: SI > 85.47 (1) and 56.53 (2). Altogether, data indicate that the anti-T. cruzi activity of 4-, 6- and 7-nitroindazolinones is not better than that of 1 and 2, not presenting significant advantages over these two 5-nitroindazolinones.
SN - 0031-1820
SN - 1469-8161
ER -