Effective discrimination of antimalarial potency of artemisinin compounds based on quantum chemical calculations of their reaction mechanism.

The reaction mechanism of 12 antimalarial artemisinin compounds with two competitive pathways was studied by means of quantum chemical calculations using the IMOMO(B3LYP/6-31(d,p):HF/3-21G) method. The oxygen-centered radicals, carbon-centered radicals, and transition states (TS) in both pathways were geometrically optimized. The obtained kinetic and thermodynamic energy profiles show that homolytic C-C cleavage reaction (pathway 2) is energetically more preferable than an intramolecular 1,5-hydrogen shift process (pathway 1), which is consistent with the docking calculations. However, compounds that can easily proceed along the pathway 1 have high activity. Therefore, both pathways are important for antimalarial activity. Moreover, effective discrimination between high and low activity compounds using EA1, deltaE1, and deltaE(1A-2A) was accomplished.