Heme alkylation by artemisinin and trioxaquines

Artemisinin is an efficient antimalarial drug containing a 1,2,4-trioxane which is able to alkylate heme both in vitro and in vivo, giving rise to covalent heme-artemisinin coupling products. The low valent iron(II) protoporphyrin-IX, which is the prosthetic group of hemoglobin, induces the homolysis of the peroxide bond of artemisinin by an electron transfer. The generated alkoxy radical is quickly rearranged to a C-centered radical that efficiently alkylates the heme macrocycle at meso positions. Heme is therefore both the activating agent and the target of artemisinin. Additionally, the iron(II) heme cofactor of carboxyhemoglobin was found to react as efficiently with artemisinin as oxyhemoglobin does, providing a heme-drug covalent adduct in up to 60% yield. This result indicates that the presence of a CO ligand bound to iron does not preclude the reductive activation of the peroxide, thereby confirming the high affinity of artemisinin for iron(II) heme. On the basis of this mechanism of action, a variety of new peroxide-based antimalarials named trioxaquines® have been synthesized. Trioxaquines are made by the covalent attachment of a trioxane, having alkylating ability, to a quinoline, known to readily penetrate infected erythrocytes. Several trioxaquines are active in vitro on chloroquine resistant malaria parasite at nanomolar concentrations, and are efficient to cure infected mice by oral route at 20–50 mg/kg. Copyright © 2006 John Wiley & Sons, Ltd.