2. Academic Validation
  3. Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi

Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi

  • J Med Chem. 2018 Jul 12;61(13):5643-5663. doi: 10.1021/acs.jmedchem.8b00468.
Rubén Martín-Escolano 1,  Elsa Moreno-Viguri 2,  Mery Santivañez-Veliz 2,  Alvaro Martin-Montes 1,  Encarnación Medina-Carmona 3,  Rocío Paucar 2,  Clotilde Marín 1,  Amaya Azqueta 4,  Nuria Cirauqui 5,  Angel L Pey 3,  Silvia Pérez-Silanes 2,  Manuel Sánchez-Moreno 1
Affiliations

Affiliations

  • 1 Departament of Parasitology , Instituto de Investigación Biosanitaria (ibs.Granada), Hospitales Universitarios De Granada/University of Granada , Severo Ochoa s/n , E-18071 Granada , Spain.
  • 2 Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical , Pamplona 31008 , Spain.
  • 3 Department of Physical Chemistry, Faculty of Sciences , University of Granada , Av. Fuentenueva s/n , 18071 Granada , Spain.
  • 4 Universidad de Navarra , Department of Pharmacology and Toxicology , Pamplona 31008 , Spain.
  • 5 Department of Pharmaceutical Sciences , Federal University of Rio de Janeiro , Rio de Janeiro 21949-900 , Brazil.
PMID: 29883536 DOI: 10.1021/acs.jmedchem.8b00468
Abstract

Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.

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