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DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2024 Oct 05; Vol. 276, pp. 116641. Date of Electronic Publication: 2024 Jul 01. - Publication Year :
- 2024
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Abstract
- Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC <subscript>50</subscript>  = 1.5-3.3 μM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.<br />Competing Interests: Declaration of competing interest The authors have no competing interests to declare.<br /> (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Ligands
Humans
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
Parasitic Sensitivity Tests
Antiparasitic Agents pharmacology
Antiparasitic Agents chemistry
Antiparasitic Agents chemical synthesis
Trypanosoma cruzi drug effects
G-Quadruplexes drug effects
Chagas Disease drug therapy
Trypanocidal Agents pharmacology
Trypanocidal Agents chemistry
Trypanocidal Agents chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 276
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38971047
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116641