Identification of a Class of Iron-Grabbing Compounds with Antiplasmodial Activity: Impact of Coordination Structures and Electronic Regularity on the Intraerythrocytic Growth Cycle of <i>Plasmodium falciparum</i>

Innovative antimalarials are required to combat malaria, a global infectious disease caused by <i>Plasmodium falciparum</i>. To explore the untapped antiplasmodial compounds that can target the iron source vital at the blood stages of <i>P. falciparum</i>, we investigated the antiplasmodial activities of natural siderophores and synthetic compounds with metal-binding affinity. The assessment of their IC₅₀ values and spectroscopic analytical data revealed that terpyridyl compounds specifically bound to target Fe(II) ions and strongly induced the growth inhibition of intraerythrocytic parasites. Furthermore, the IC₅₀ values of the 4,4',4''-substituted terpyridines were linearly correlated with the sum of the <i>para</i> Hammett constants of their substitutions, suggesting that their growth inhibitory effects depended on the electronic states of the coordinating nitrogen atoms. Considering the specific developmental blockage at the trophozoite stage and selective antiplasmodial activities of the iron-grabbing compounds, these findings provide insights into the development of antimalarials that can disrupt iron homeostasis.