2. Academic Validation
  3. Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation

Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation

  • Bioorg Med Chem. 2019 Sep 1;27(17):3902-3917. doi: 10.1016/j.bmc.2019.07.029.
Rocío Paucar 1,  Rubén Martín-Escolano 2,  Elsa Moreno-Viguri 1,  Amaya Azqueta 3,  Nuria Cirauqui 4,  Clotilde Marín 2,  Manuel Sánchez-Moreno 2,  Silvia Pérez-Silanes 5
Affiliations

Affiliations

  • 1 Universidad de Navarra, Department of Pharmaceutical Technology and Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain.
  • 2 Department of Parasitology, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/University of Granada, Granada 18071, Spain.
  • 3 Universidad de Navarra, Department of Pharmacology and Toxicology, Pamplona 31008, Spain.
  • 4 Department of Pharmaceutical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, Brazil.
  • 5 Universidad de Navarra, Department of Pharmaceutical Technology and Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain. Electronic address: sperez@unav.es.
PMID: 31345745 DOI: 10.1016/j.bmc.2019.07.029
Abstract

The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD Enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.

Keywords

Chagas disease; Mannich bases; Superoxide dismutase; Trypanosoma cruzi.

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