Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
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Le résumé fourni par la source
High Resolution Image Download MS PowerPoint Slide Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC 50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC 50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Synthesis and Anti-<i>Trypanosoma cruzi</i> Activity of 3-Cyanopyridine Derivatives
- Date Crossref
- 13/05/2024
- Éditeur
- American Chemical Society (ACS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Universidade Estadual de Campinas (UNICAMP) pays non établi dans la noticeUniversité ou école supérieure
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University of Antwerp Laboratory of Microbiology pays non établi dans la noticeUniversité ou école supérieure
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Universidade de São Paulo pays non établi dans la noticeUniversité ou école supérieure
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Drugs for Neglected Diseases Initiative pays non établi dans la noticeOrganisation à but non lucratif
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State University of Campinas Institute of Chemistry pays non établi dans la noticeUniversité ou école supérieure
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University of Sao Paulo Laboratory of Medicinal and Computational Chemistry pays non établi dans la noticeUniversité ou école supérieure
Universidade Estadual de Campinas (UNICAMP), Laboratory of Microbiology — University of Antwerp et Universidade de São Paulo, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.