Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities

Historically, the most successful molecular target for antimalarial drugs has been heme biomineralization within the malarial parasite digestive vacuole. Heme released from catabolized host red blood cell hemoglobin is toxic, so malarial parasites crystallize heme to nontoxic hemozoin. For years it has been accepted that a number of effective quinoline antimalarial drugs (e.g., chloroquine, quinine, amodiaquine) function by preventing hemozoin crystallization. However, recent studies over the past decade have revealed a surprising molecular diversity in quinoline-heme molecular interactions. This diversity shows that even closely related quinoline drugs may have quite different molecular pharmacology. This paper reviews the molecular diversity and highlights important implications for understanding quinoline antimalarial drug resistance and for future drug design.