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Synthesis and evaluation of in vitro and in vivo trypanocidal properties of a new imidazole-containing nitrophthalazine derivative.
Synthesis and evaluation of in vitro and in vivo trypanocidal properties of a new imidazole-containing nitrophthalazine derivative.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2015 Dec 01; Vol. 106, pp. 106-19. Date of Electronic Publication: 2015 Oct 23. - Publication Year :
- 2015
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Abstract
- A series of new phthalazine derivatives (1-4) containing imidazole rings and functionalized with nitro groups in the benzene ring of the phthalazine moiety were prepared and identified on the basis of their MS, elemental analyses and bidimensional (1)H and (13)C NMR data, and their trypanocidal activity was tested. The 8-nitrosubstituted compound (3) was more active in vitro against Trypanosoma cruzi and less toxic against Vero cells than the reference drug benznidazole, and showed a SI value that was 47-fold better than the reference drug in amastigote forms. It also remarkably reduced the infectivity rate in Vero cells and decreased the reactivation of parasitemia in immunodeficient mice. Ultrastructural alterations found in epimastigotes treated with 3 confirmed extensive cytoplasm destruction in the parasites, whereas histopathological analysis of the hearts of mice infected and treated with 3 resulted in a decrease in cardiac damage. Biochemical markers showed that livers, hearts, and kidneys of treated mice were substantially unaffected by the administration of 3, despite the presence of the potentially toxic nitro group. It was also found that this compound selectively inhibited the antioxidant parasite enzyme Fe-superoxide dismutase (Fe-SOD) in comparison with human CuZn-SOD, and molecular modeling suggested interaction with the H-bonding system of the iron-based moiety as a feasible mechanism of action against the enzyme.<br /> (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Chlorocebus aethiops
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Female
Humans
Imidazoles chemical synthesis
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Structure
Parasitemia parasitology
Phthalazines chemical synthesis
Phthalazines chemistry
Structure-Activity Relationship
Superoxide Dismutase antagonists & inhibitors
Superoxide Dismutase metabolism
Trypanocidal Agents chemical synthesis
Trypanosoma cruzi enzymology
Vero Cells
Enzyme Inhibitors pharmacology
Imidazoles chemistry
Imidazoles pharmacology
Parasitemia drug therapy
Phthalazines pharmacology
Trypanocidal Agents chemistry
Trypanocidal Agents pharmacology
Trypanosoma cruzi drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 106
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26523668
- Full Text :
- https://doi.org/10.1016/j.ejmech.2015.10.034