Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker

Abstract: Based on the prodrug concept as well as the combination of two different classes of antimalarial agents, we designed and synthesized two series of ferrocenic antimalarial dual molecules consisting of a ferroquine analogue conjugated with a glutathione reductase inhibitor (or a glutathione depletor) through a cleavable amide bond in order to target two essential pathways in the malarial parasites. The results showed no enhancement of the antimalarial activity of the dual molecules but evidenced a unique mode of action of ferroquine and ferrocenyl analogues distinct of those of chloroquine and nonferrocenic 4-aminoquinoline analogues. [Copyright &y& Elsevier]