Chemical Instability Determines the Biological Action of the Artemisinins

Abstract

Artemisinin is a sesquiterpene compound of plant origin. It has a low molecular weight, and it contains five oxygen atoms, two in a lactone function, one is part of a seven membered ring system and two forms a peroxide function bridging over the seven-membered ring. It is a highly energetic molecule prone to lose its activity if circumstances permit. Reduction of its lactone function into dihydroartemisinin makes derivatization easy. Esterification and ether formation contribute to stability. Dihydroartemisinin exists preferably in a beta epimeric format but flip-flops with the alpha epimer. Solvation effects play a role. In doing so, open forms are created and they contribute to the instability, both of the peroxide and of the seven-membered ring. Artemisinins constitute a remarkable class of compounds which display instability both biologically and chemically due to the presence of various functional groups. Activity ranges from a wonderful action against a series of parasites, in particular malaria and schistosomiasis, to bacteria, fungi and selected viruses. The latest developments indicate a potential use in adjuvant cancer chemotherapy. The built-in chemical instability, necessary for biological action, causes serious pharmaceutical problems and only a restricted number of derivatives are useful. Problems are accelerated under tropical conditions and the basic active drug dihydroartemisinin cannot be used as such since it is prone to accelerated breakdown into a series of inactive products. The pitfalls of chemical instability and pharmaceutical stability are discussed in relation to the current uses of the drugs.

A liquid chromatographic-tandem mass spectrometric method for determination of artesunate and its metabolite dihydroartemisinin in human plasma

“…When testing stability of these two compounds it is important to recognize that the primary route of ARS degradation is through formation of DHA. ARS can form DHA both through chemical hydrolysis and through plasma esterase mediated hydrolysis [11,29]. The stability of the drugs in different sources of plasma is very variable [30].…”

In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon

“…Its pharmacophore is the characteristic peroxide bond sitting in a trioxane connection. Artemisinin itself shows poor oral availability, poor solubility both in water and oil, and is less active than its derivatives [3,4]. Dihydroartemisinin (DHA) is a derivative of artemisinin obtained by chemical reduction that is more active than artemisinin itself but is thermally less stable [5].…”

Major pitfalls in the measurement of artemisinin derivatives in plasma in clinical studies

“…The exact mechanism of antimalarial action of artemisinin and analogues is still a subject of intense debate. However there seems to be consensus that a cation-dependent reaction with the reactive peroxide bridge and the production of free radicals or other reactive intermediates is crucial for antimalarial activity [4][5][6][7]. The main cation implicated is thought to be ferrous iron (II).…”