DFT study of the reductive decomposition of artemisinin Original Research Article

Artemisinin is a sesquiterpene lactone with an endoperoxide function that is essential for its antimalarial activity. The DFT B3LYP method, together with the 6-31G(d) and 6-31+G(d,p) basis set, is employed to calculate a set of radical anions and neutral species supposed to be formed during the rearrangement of artemisinin from the two radicals (C-centered and O-centered) that are supposed to play a relevant role in the mechanism of action. The B3LYP results show that the primary and the secondary radicals centered on C4, generated by homolytic break of the C3–C4 bond and by 1,5 hydrogen shift, respectively, are more stable than radicals centered on oxygen. The calculations show that the activation barriers for rearrangements are low, leading to a thermodynamically favorable process. These results reinforce our previous conclusions based on semi-empirical calculations but also give additional information on the reductive decomposition of artemisinin.