2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2017 Aug 18:136:223-234. doi: 10.1016/j.ejmech.2017.04.075.
Angela Guerra 1,  Pedro Gonzalez-Naranjo 1,  Nuria E Campillo 2,  Javier Varela 3,  María L Lavaggi 3,  Alicia Merlino 3,  Hugo Cerecetto 3,  Mercedes González 3,  Alicia Gomez-Barrio 4,  José A Escario 4,  Cristina Fonseca-Berzal 4,  Gloria Yaluf 5,  Jorge Paniagua-Solis 6,  Juan A Páez 7
Affiliations

Affiliations

  • 1 Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
  • 2 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 3 Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
  • 4 Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza, Ramón y Cajal s/n, 28040, Madrid, Spain.
  • 5 Instituto de Investigaciones en Ciencias de la Salud (iics), Universidad Nacional de Asunción, Asunción, Paraguay.
  • 6 Laboratorios Silanes IDF, S.L. Calle Santiago Grisolia, Nº 2- PTM 148 Parque Tecnologico de Madrid 28760, Tres Cantos, Madrid, Spain.
  • 7 Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: jpaez@iqm.csic.es.
PMID: 28499168 DOI: 10.1016/j.ejmech.2017.04.075
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.

Keywords

CODES(®); Chagas disease; Imidazo[4,5-c][1,2,6]thiadiazine; Neural network; Trypanocidal; Trypanosoma cruzi.

Figures