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Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Sep 01; Vol. 27 (17), pp. 3902-3917. Date of Electronic Publication: 2019 Jul 19. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
Chagas Disease metabolism
Chlorocebus aethiops
Cyclophosphamide administration & dosage
Cyclophosphamide pharmacology
Dose-Response Relationship, Drug
Humans
Injections, Intraperitoneal
Mannich Bases chemical synthesis
Mannich Bases chemistry
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
Parasitic Sensitivity Tests
Structure-Activity Relationship
Superoxide Dismutase metabolism
Trypanocidal Agents chemical synthesis
Trypanocidal Agents chemistry
Trypanosoma cruzi metabolism
Vero Cells
Chagas Disease drug therapy
Mannich Bases pharmacology
Superoxide Dismutase antagonists & inhibitors
Trypanocidal Agents pharmacology
Trypanosoma cruzi drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 27
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31345745
- Full Text :
- https://doi.org/10.1016/j.bmc.2019.07.029