The in Vitro Antiplasmodial and Antiproliferative ...
Document type :
Article dans une revue scientifique
DOI :
Permalink :
Title :
The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction
Author(s) :
Mbaba, Mziyanda [Auteur]
Rhodes University, Grahamstown
Dingle, Laura M. K. [Auteur]
Rhodes University, Grahamstown
Swart, Tarryn [Auteur]
Rhodes University, Grahamstown
Cash, Devon [Auteur]
Rhodes University, Grahamstown
Laming, Dustin [Auteur]
Rhodes University, Grahamstown
de la Mare, Jo‐Anne [Auteur]
Rhodes University, Grahamstown
Taylor, Dale [Auteur]
University of Cape Town
Hoppe, Heinrich C. [Auteur]
Rhodes University, Grahamstown
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Edkins, Adrienne L. [Auteur]
Rhodes University, Grahamstown
Khanye, Setshaba D. [Auteur]
Rhodes University, Grahamstown
Rhodes University, Grahamstown
Dingle, Laura M. K. [Auteur]
Rhodes University, Grahamstown
Swart, Tarryn [Auteur]
Rhodes University, Grahamstown
Cash, Devon [Auteur]
Rhodes University, Grahamstown
Laming, Dustin [Auteur]
Rhodes University, Grahamstown
de la Mare, Jo‐Anne [Auteur]
Rhodes University, Grahamstown
Taylor, Dale [Auteur]
University of Cape Town
Hoppe, Heinrich C. [Auteur]
Rhodes University, Grahamstown
Biot, Christophe [Auteur]
![refId](/themes/Mirage2//images/idref.png)
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Edkins, Adrienne L. [Auteur]
Rhodes University, Grahamstown
Khanye, Setshaba D. [Auteur]
Rhodes University, Grahamstown
Journal title :
ChemBioChem
Abbreviated title :
https://lilloa.univ-lille.fr/handle/20.500.12210/33ChemBioChem
Volume number :
21
Pages :
2643-2658
Publisher :
Wiley
Publication date :
2020-05-27
English keyword(s) :
Aminocresols
breast cancer
DNA interactions
ferrocene
hemozoin inhibition
Plasmodium falciparum
breast cancer
DNA interactions
ferrocene
hemozoin inhibition
Plasmodium falciparum
HAL domain(s) :
Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique
Chimie/Chimie théorique et/ou physique
English abstract : [en]
The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation ...
Show more >The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.Show less >
Show more >The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CNRS
CNRS
Research team(s) :
Chemical Glycobiology
Submission date :
2021-01-28T13:36:27Z
2021-02-08T17:37:14Z
2021-02-08T17:37:14Z
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