DFT study of the reductive decomposition of artemisinin

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 C 4 , generated by homolytic break of the C 3 –C 4 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.