Alkylating properties of antimalarial artemisinin derivatives and synthetic trioxanes when activated by a reduced heme model

Three potent antimalarial drugs bearing a trioxane function, artemisinin, beta-artemether, and a synthetic analogue BO7, were found to behave as alkylating agents towards a heme model, meso-tetraphenylporphyrin. The covalent chlorin - drug adducts obtained between these drugs and the macrocycle were completely characterized. These adducts resulted from a C-alkylation of a beta-pyrrolic position of the porphyrin macrocycle by a C-centered radical produced by the reductive homolytic cleavage of the peroxide bridge of artemisinin or its analogues. The results indicate that the alkylating properties of artemisinin, which are considered to be responsible for the death of the parasite, are not limited to this natural compound, but are a common feature probably required for the antimalarial activity of endoperoxide-containing drugs.