The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction - Université de Lille Accéder directement au contenu
Article Dans Une Revue ChemBioChem Année : 2020

The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction

Résumé

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.
Fichier principal
Vignette du fichier
P20.30 The in Vitro Antiplasmodial and Antiproliferative Activity .pdf (839.99 Ko) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03135213 , version 1 (08-02-2021)

Identifiants

Citer

Mziyanda Mbaba, Laura M. K. Dingle, Tarryn Swart, Devon Cash, Dustin Laming, et al.. The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene‐Based α‐Aminocresols Targeting Hemozoin Inhibition and DNA Interaction. ChemBioChem, 2020, 21 (18), pp.2643-2658. ⟨10.1002/cbic.202000132⟩. ⟨hal-03135213⟩

Collections

CNRS UNIV-LILLE
29 Consultations
107 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More