Pyronaridine (PYR) is an erythrocytic schizonticide with a potent
antimalarial activity against multidrug-resistant Plasmodium. The drug is used in combination with
artesunate for the treatment of uncomplicated P.
falciparum malaria, in adults and children. The present review briefly retraces the discovery of PYR and recent
antimalarial studies which has led to the approval of PYR/
artesunate combination (
Pyramax) by the European Medicines Agency to treat uncomplicated
malaria worldwide. PYR also presents a marked antitumor activity and has revealed efficacy for the treatment of other
parasitic diseases (notably Babesia and Trypanosoma
infections) and to mitigate the Ebola virus propagation. On the one hand, PYR functions has an inhibitor of
hemozoin (biomineral
malaria pigment, by-product of
hemoglobin digestion) formation, blocking the biopolymerization of β-
hematin and thus facilitating the accumulation of toxic
hematin into the digestive vacuole of the parasite. On the other hand, PYR is a bona fide
DNA-
intercalating agent and an inhibitor of
DNA topoisomerase 2, leading to
DNA damages and cell death. Inhibition of
hematin polymerization represents the prime mechanism at the origin of the
antimalarial activity, whereas anticancer effects relies essentially on the interference with
DNA metabolism, as with structurally related anticancer drugs like
amsacrine and
quinacrine. In addition, recent studies point to an immune modulatory activity of PYR and the implication of a mitochondrial oxidative pathway. An analogy with the mechanism of action of
artemisinin drugs is underlined. In brief, the biological actions of
pyronaridine are recapitulated to shed light on the diverse health benefits of this unsung drug.