Biological actions of artemisinin: insights from medicinal chemistry studies

Abstract

Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions, including alkylation of heme by carbon-centered free radicals, interference with proteins such as the sarcoplasmic/endoplasmic calcium ATPase (SERCA), as well as damaging of normal mitochondrial functions. Besides artemisinins, other endoperoxides with various backbones have also been synthesized, some of which showed comparable or even higher antimalarial effects. It is noteworthy that among these artemisinin derivatives, some enantiomers displayed similar in vitro malaria killing efficacy. In this article, the proposed mechanisms of action of artemisinins are reviewed in light of medicinal chemistry findings characterized by efficacy-structure studies, with the hope of gaining more insight into how these potent drugs work.

Figure 1

Structures of artemisinin and its analogues. (a) Artemisinin. (b) An early derived peroxide with less antimalarial potency. (c) An analogue with close structure to artemisinin. (d) An antimalarial tetraoxane. (e) OZ277. (f, g and h) Enantiomers with similar activities against malaria parasites. (i) thapsigargin.

Figure 2

Proposed biological models for the action of artemisinin (Art). (a) The PfATP6 model: artemisinin undergoes activation by reacting with catalytic iron, and after non-covalent specific interaction with PfATP6, the formed free radicals then exert irreversible damage to this target protein. (b) The heme model: artemisinin is activated by heme, followed by alkylation of heme and/or other malarial proteins. (c) The mitochondria model: malarial mitochondria specifically activate artemisinin. The activated artemisinin then induces free radicals production and mitochondrial membrane depolarization. No specific protein targets are implicated.