247. “The design and synthesis of new artemisinin analogues”
     Jefford, C.
     Jpn. J. Trop. Med. Hyg. 1996, 24, 7-11.

The design and synthesis of an effective, antiperoxidic antimalarial agent depends on an understandingof the mode of action of artemisinin (1) and the provision of appropriate technology for constructing the simplestmolecule 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 trioxanesare described in which ferrous salts are used as a substitute for heme. Rapid isomerization occurs through theintermediacy 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 antimalarialactivity. The synthesis of new artemisinin analogues will be discussed in the light of this criterion. The role of ironand copper salts on the oxygenative conversion of artemisinic acid to 1 will also be reviewed.

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