Insight into the mechanism of the antimalarial action of plakortins, simple 1,2-dioxane antimalarials

A multidisciplinary approach, based on mol. dynamics/mechanics, ab initio calcns., dynamic docking studies, and chem. reactions, has been employed to gain insight into the mechanism of the antimalarial action of plakortin and dihydroplakortin, simple 1,2-dioxanes isolated from the sponge Plakortis simplex. Our results show that these mols., after interaction of the endoperoxide bond with Fe(II), likely coming from the heme mol., give rise to the formation of an oxygen radical, followed by rearrangement to give a carbon radical centered on the "western" alkyl side-chain. The carbon radicals generated on the side-chain, amenable for intermol. reactions, should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The minimal structural requirements necessary for the activity of this class of antimalarial agents have been identified and discussed throughout the paper.