New Pd–Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands: a comparative study with their Pt–Fe analogues†

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Título

New Pd–Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands: a comparative study with their Pt–Fe analogues†

Tema

ANTIPARASITARIOS
TRYPANOSOMA BRUCEI
PARASITOS
QUIMIOTERAPIA
BIBLIOGRAFIA NACIONAL QUIMICA
2021

Abstract

In the search for a more effective chemotherapy for the treatment of Human African Trypanosomiasis, a disease caused by the parasite Trypanosoma brucei, the development of ferrocenyl compounds has arisen as a promising strategy. In this work, five new Pd–Fe heterobimetallic [PdII(L)(dppf)](PF6) compounds, including 8-hydroxyquinolyl derivatives HL1–HL5 as bioactive ligands and dppf = 1,1’-bis(diphenylphosphino)
ferrocene as the organometallic co-ligand, were synthesized and fully characterized in the solid state and in solution. Molecular structures of three compounds were solved by single crystal X-ray diffraction methods. The compounds displayed submicromolar or micromolar IC50 values against bloodstream
T. brucei (IC50: 0.33–1.2 μM), and good selectivity towards the pathogen (SI: 4–102) with respect to mammalian macrophages (cell line J774). The new Pd complexes proved to be 2-fold to 45-fold more potent than the drug nifurtimox but most of them are less active than their Pt analogues. Potential molecular
targets were studied. The complexes interact with DNA but they do not alter the intracellular thiolredox homeostasis of the parasite. In order to understand and predict the main structural determinants on the anti-T. brucei activity, a search of quantitative structure–activity relationships (QSAR) was performed including all the [M(L)(dppf)](PF6) complexes, where M = Pd(II) or Pt(II), currently and previously
developed by us. The correlation obtained shows the relevance of the electronic effects, the lipophilicity and the type of metal. According to the QSAR study, compounds with electron-withdrawing ligands, higher lipophilicity and harboring Pt would result in higher T. brucei cytotoxicity. From the whole series of
[M(L)(dppf)](PF6) compounds developed, where M = Pt(II) or Pd(II) and HL = 8-hydroxyquinolyl derivatives, Pt-dppf-L4 (IC50 = 0.14 μM, SI = 48) was selected to perform an exploratory pre-clinical study in infected mice. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described and exerts an anti-proliferative effect on parasites, which extends animal survival but is not curative.

Autor

Rivas, Feriannys
Medeiros, Andrea
Quiroga, Cristina
Benítez, Diego
Comini, Marcelo
Rodríguez Arce, Esteban
Machado, Ignacio
Cerecetto, Hugo
Gambino, Dinorah

Fuente

Dalton Transactions, v. 50, n° 5, 2021.-- pp. 1651-1665.

Editor

Royal Society of Chemistry

Fecha

2021

Derechos

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PDF

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Inglés

Tipo

Artículo

Identificador

10.1039/d0dt03963b 

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PDF
Fecha de agregación
October 22, 2021
Colección
Bibliografía Nacional Química
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Document
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Citación
Rivas, Feriannys, “New Pd–Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands:a comparative study with their Pt–Fe analogues†,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed December 8, 2021, http://riquim.fq.edu.uy/items/show/6413.
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