Artemisinin, a sesquiterpene peroxide isolated from Artemisia annua, and its derivatives are our most useful antimalarials. Their history, development and clinical efficacy are reviewed.

The proposed mechanisms of action of artemisinin have been intensively discussed. These include the involvement of reactive oxygen species (ROS) to increase oxidative stress within parasites, the formation of carbon-centred radicals arising via a Fenton process on the peroxide that are held to destroy crucial biomolecules, and the binding of the intact artemisinins to malaria-SERCA PfATP6. However, each of the hypotheses is accompanied by unresolved issues. Establishment of the actual mechanism is indispensable as it will enable optimization of the antimalarial efficacy of the artemisinins, h...[ Read more ]

Artemisinin, a sesquiterpene peroxide isolated from Artemisia annua, and its derivatives are our most useful antimalarials. Their history, development and clinical efficacy are reviewed.

The proposed mechanisms of action of artemisinin have been intensively discussed. These include the involvement of reactive oxygen species (ROS) to increase oxidative stress within parasites, the formation of carbon-centred radicals arising via a Fenton process on the peroxide that are held to destroy crucial biomolecules, and the binding of the intact artemisinins to malaria-SERCA PfATP6. However, each of the hypotheses is accompanied by unresolved issues. Establishment of the actual mechanism is indispensable as it will enable optimization of the antimalarial efficacy of the artemisinins, help to minimize toxicity and very importantly open a way to monitor for resistance to artemisinins in parasites. In this thesis, the molecular mechanism of action of artemisinin is explored from two aspects. It has been proposed that artemisinins exert their antimalarial effect by binding to PfATP6, a protein which regulates the transportation of calcium ions within the cells. Artemisone, a relatively new 10-amino-substituted artemisinin derivative discovered by our group, inhibits PfATP6 at a nanomolar level. As the binding should be very sensitive to structural differences, the enantiomer of artemisone has to be prepared to test the efficacy of the binding. The total synthesis of this unnatural enantiomer was therefore commenced. However, a roadblock in the synthesis appeared – the failure of the conjugate addition of the enolate of (1S, 3S, 4R, 8S)-9-(phenylmethoxy)-p-menthone to a trimethylsilyl derivative of methyl vinyl ketone. This resulted in a preliminary study of the conformation of the enolate, and the circumstances surrounding the failure of the conjugate addition.

A novel pathway involving artemisinins acting as parasiticidal agents without iron has also been investigated. The antimalarial activity may arise through their knocking out some vital enzyme cofactors. Artemisinins may act as antimalarial drugs by perturbing redox balance within the malaria parasite, both by oxidizing FADH₂ in parasite glutathione reductase (GR) or other parasite flavoenzymes, and by initiating autooxidation of the dihydroflavin by oxygen with generating of ROS, and hence ultimately causing the depletion of NAD(P)H. In this research, artemisinins were decomposed by leucomethylene blue and dihydroflavin produced in situ from methylene blue-ascorbic acid and flavin-BNAH (or NAD(P)H) respectively. According to the studies, artemisinins act both as one-electron transfer agents and two-electrons acceptors, in the absence of iron, and are most likely to exert their parasiticidal effects in this way.