Artemisinins are derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, including highly drug-resistant strains. Their efficacy also extends to phylogenetically unrelated parasitic infections such as schistosomiasis. More recently, they have also shown potent and broad anticancer properties in cell lines and animal models. In this review, we discuss recent advances in defining the role of artemisinins in medicine, with particular focus on their controversial mechanisms of action. This safe and cheap drug class that saves lives at risk from malaria can also have important potential in oncology.

Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced.

The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous - in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t1/2 26 min, and at pH 7.4, t1/2 is about 10 hours. With a pKa of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the druggability of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.