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

Abstract

Conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. Herein, we present the in vitro antimalarial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and the α‐aminocresol scaffold. The compounds pursued in the study exhibited higher toxicity towards the susceptible (3D7) and resistant (Dd2) strains of the Plasmodium falciparum parasite than 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. The compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor groove binding. Lastly, compound 9a, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antimalarial activity. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multi‐modal compounds with potential to counter drug resistance development.