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Trypanosoma cruzi killing and immune response boosting by novel phenoxyhydrazine-thiazole against Chagas disease.
- Source :
-
Experimental parasitology [Exp Parasitol] 2024 Jun; Vol. 261, pp. 108749. Date of Electronic Publication: 2024 Apr 07. - Publication Year :
- 2024
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Abstract
- Trypanosoma cruzi (T. cruzi) causes Chagas, which is a neglected tropical disease (NTD). WHO estimates that 6 to 7 million people are infected worldwide. Current treatment is done with benznidazole (BZN), which is very toxic and effective only in the acute phase of the disease. In this work, we designed, synthesized, and characterized thirteen new phenoxyhydrazine-thiazole compounds and applied molecular docking and in vitro methods to investigate cell cytotoxicity, trypanocide activity, nitric oxide (NO) production, cell death, and immunomodulation. We observed a higher predicted affinity of the compounds for the squalene synthase and 14-alpha demethylase enzymes of T. cruzi. Moreover, the compounds displayed a higher predicted affinity for human TLR2 and TLR4, were mildly toxic in vitro for most mammalian cell types tested, and LIZ531 (IC50 2.8 μM) was highly toxic for epimastigotes, LIZ311 (IC50 8.6 μM) for trypomastigotes, and LIZ331 (IC50 1.9 μM) for amastigotes. We observed that LIZ311 (IC50 2.5 μM), LIZ431 (IC50 4.1 μM) and LIZ531 (IC50 5 μM) induced 200 μg/mL of NO and JM14 induced NO production in three different concentrations tested. The compound LIZ331 induced the production of TNF and IL-6. LIZ311 induced the secretion of TNF, IFNγ, IL-2, IL-4, IL-10, and IL-17, cell death by apoptosis, decreased acidic compartment formation, and induced changes in the mitochondrial membrane potential. Taken together, LIZ311 is a promising anti-T. cruzi compound is not toxic to mammalian cells and has increased antiparasitic activity and immunomodulatory properties.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Inhibitory Concentration 50
Membrane Potential, Mitochondrial drug effects
Hydrazines pharmacology
Hydrazines chemistry
Cytokines metabolism
Mice, Inbred BALB C
Trypanosoma cruzi drug effects
Thiazoles pharmacology
Thiazoles chemistry
Chagas Disease drug therapy
Chagas Disease immunology
Nitric Oxide metabolism
Nitric Oxide biosynthesis
Molecular Docking Simulation
Trypanocidal Agents pharmacology
Trypanocidal Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2449
- Volume :
- 261
- Database :
- MEDLINE
- Journal :
- Experimental parasitology
- Publication Type :
- Academic Journal
- Accession number :
- 38593864
- Full Text :
- https://doi.org/10.1016/j.exppara.2024.108749