Fluoroartemisinin:: Trifluoromethyl analogues of artemether and artesunate

The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF3 analogues of beta-artemether, beta-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF3 group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. For example, the CF3 analogue of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF3 moiety on biological activity was also highlighted. CF3 analogues of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).