The design and synthesis of new artemisinin analogues

The design and synthesis of an effective, antiperoxidic antimalarial agent depends on an understanding of the mode of action of artemisinin (1) and the provision of appropriate technology for constructing the simplest molecule that fulfils the mechanistic criteria. It is believed that 1 and its congeners kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Model experiments with 1, β-artemether, and certain synthetic trioxanes are described in which ferrous salts are used as a substitute for heme. Rapid isomerization occurs through the intermediacy of a C-centered radical. It is inferred that analogous heme-generated radicals kill the parasite by alkylation. Consequently, ferrous ion-promoted isomerization of peroxides can be used as a criterion for antimalarial activity. The synthesis of new artemisinin analogues will be discussed in the light of this criterion. The role of iron and copper salts on the oxygenative conversion of artemisinic acid to 1 will also be reviewed.