Theoretical investigations on reaction mechanisms of artemisinin compounds: effect of structure on kinetic energy profile and antimalarial activity

The reaction mechanisms of three structurally different antimalarial artemisinin compounds with two competitive pathways were investigated by means of quantum chemical calculations using the IMOMO(B3LYP/6-31G(d,p):HF/3-21G) method. The oxygen-centered radicals, the carbon-centered radicals, and the transition states (TS) in both pathways were geometry optimized. The results reveal that the homolytic C-C cleavage reaction (pathway 2) is energetically more preferable than the intramolecular 1,5-hydrogen shift process (pathway 1), which is consistent with the experimental results and the docking calculations. However, the 1,5-H shift process is likely to be essential for a high antimalarial activity as evidenced by the fact that artemisinin is energetically more difficult to proceed along the pathway 1 than the other two compounds due to different kinetic energy profiles and hence it has lower activity.