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Título: | 5-Nitroindazole-based compounds: further studies for activity optimization as anti-Trypanosoma cruzi agents |
Autor: | Fonseca-Berzal, Cristina; Ibáñez-Escribano, Alexandra; Castro, Sonia de CSIC ORCID; Escario, José A.; Gómez-Barrio, Alicia; Arán, Vicente J. CSIC ORCID | Palabras clave: | Chagas disease Indazole Nitroheterocycle In silico In vitro |
Fecha de publicación: | 2022 | Editor: | Elsevier | Citación: | Acta Tropica 234 : 106607 (2022) | Resumen: | In this study, a new series of eleven 5-nitroindazole derivatives (10−20) and a related 6-nitroquinazoline (21) was synthesized and tested in vitro against different forms of the kinetoplastid parasite Trypanosoma cruzi, etiological agent of Chagas disease. Among these compounds, derivatives 11−14 and 17 showed trypanocidal profiles on epimastigotes (IC50 = 1.00−8.75 µM) considerably better than that of the reference drug benznidazole, BZ (IC50 = 25.22 µM). Furthermore, the lack of cytotoxicity observed for compounds 11, 12, 14, 17 and 18 over L929 fibroblasts, led to a notable selectivity (SI) on the extracellular replicative form of the parasite: SIEPI > 12.41 to > 256 µM. Since these five derivatives overpassed the cut-off value established by BZ (SIEPI ≥ 10), they were moved to a more specific assay against the intracellular and replicative form of T. cruzi, i.e, amastigotes. These molecules were not as active as BZ (IC50 = 0.57 µM) against this parasite form; however, all of them showed remarkable IC50 values lower than 7 µM. Special mention deserve compounds 12 and 17, whose SIAMA were > 246.15 and > 188.23, respectively. The results compiled in the present work, point to a positive impact over the trypanocidal activity of the electron withdrawing substituents introduced at position 2 of the N-2 benzyl moiety of these compounds, especially fluorine, i.e., derivatives 12 and 17. These outcomes, supported by the in silico prediction of good oral bioavailability and suitable risk profile, reinforce the 5-nitroindazole scaffold as an adequate template for preparing potential antichagasic agents. | Versión del editor: | https://doi.org/10.1016/j.actatropica.2022.106607 | URI: | http://hdl.handle.net/10261/279866 | DOI: | 10.1016/j.jand.2021.04.020 |
Aparece en las colecciones: | (IQM) Artículos |
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