1. Novel Imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxides as antiproliferative trypanosoma cruzi drugs: Computational screening from neural network, synthesis and in vivo biological properties.
- Author
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Guerra A, Gonzalez-Naranjo P, Campillo NE, Varela J, Lavaggi ML, Merlino A, Cerecetto H, González M, Gomez-Barrio A, Escario JA, Fonseca-Berzal C, Yaluf G, Paniagua-Solis J, and Páez JA
- Subjects
- Animals, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Fibroblasts drug effects, Imidazoles chemical synthesis, Imidazoles chemistry, Macrophages drug effects, Mice, Molecular Structure, Structure-Activity Relationship, Thiadiazines chemical synthesis, Thiadiazines chemistry, Trypanosoma cruzi cytology, Trypanosoma cruzi growth & development, Imidazoles pharmacology, Neural Networks, Computer, Thiadiazines pharmacology, Trypanosoma cruzi drug effects
- Abstract
A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox. In vitro assays were performed to study their effects on the growth of the epimastigote form of the Tulahuen 2 strain, as well as the epimastigote and amastigote forms of CL clone B5 of Trypanosoma cruzi. To verify selectivity towards parasite cells, the non-specific cytotoxicity of the most relevant compounds was studied in mammalian cells, i.e. J774 murine macrophages and NCTC clone 929 fibroblasts. Furthermore, these compounds were assayed regarding the inhibition of cruzipain. In vivo studies revealed that one of the compounds, 19, showed interesting trypanocidal activity, and could be a very promising candidate for the treatment of Chagas disease., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2017
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