Endoperoxides antimalarial activities

In 1972, Chinese researchers isolated, by extraction at low temperature from a plant, a crystalline compound that they named qinghaosu [the name artemisinin (la) is preferred by Chemical Abstracts, RN 63968-64-9]. The plant source of artemisinin is a herb, Artemisia annua (Sweet wormwood), and the fact that artemisinin is a stable, easily crystallizable compound renders the extraction and purification processes reasonably straightforward. The key pharmacophore of this natural product is the 1,2,4-trioxane unit (2) and, in particular, the endoperoxide bridge. Reduction of the peroxide bridge to an ether provides an analogue, deoxyartemisinin 3, that is devoid of antimalarial activity. ... 

It should be emphasized that virmaUy all of the above discussion is based on biomimetic chemistry, where the Fe(II) source varies from salts such FeS04 to the more reactive FeCla-THaO as well as heme mimetics (TPP) and ester hematin variants. When heme models are used, since porphyrin alkylation is a favoured process, end-product distributions of products can be very different from when a free ferrous ion source is employed. Furthermore, solvent has been shown to have a profound effect on the rate of reaction and product distributions obtained in iron-mediated endoperoxide degradation. Thus all of these studies are truly only approximate models of the actual events within the malaria parasites. Future work is needed to correlate the results of biomimetic chemistry with the actual situation within the parasite. In general, most workers do accept the role of carbon-centred radicals in mediating the antimalarial activity of the endoperoxides, but the key information defining (a) the chemical mechanism by which these species alkylate proteins and (b) the basis for the high parasite selectivity remains to be unequivocally established. 

In effect, antimalarial trojan horse drugs of this type should deliver a double blow to the parasite by exploiting the presence of high concentrations of ferrous ion present in the parasite food vacuole as the trigger for protease inhibitor release. In model studies with prototype 81d, in the presence of ferrous ions, these systems readily degrade to produce the desired chalcone (82b, R = H, in 45% yield from 81d), in tandem with secondary carbon-centred radical 82a (Scheme 29). Furthermore, analogues 81d-f have superior in vitro antimalarial activity to that of arteflene (<25 nM in vitro versus Plasmodium falciparum, arteflene >50 nM). The other product obtained is the diol (82c), a product of two-electron reduction of the endoperoxide bridge. 

TABLE 1. Lead synthetic endoperoxide antimalarials (The table compares the antimalarial activities, the method of synthesis and the number of synthetic steps required for dmg synthesis)... 

VII. ANTI MALARIAL ACTIVITIES OF SYNTHETIC ENDOPEROXIDE ANTIMALARIALS... 

Artemisinin (23), isolated from a Chinese medicinal plant, annual wormwood Artemisia annua L.), is a unique sesquiterpene lactone bearing an endoperoxide moiety. This compound displays a strong antimalarial activity and inhibits seed germination and plant growth.11... 

It was later reported that both metabolic activation (reduction of the endoperoxide bridge) and the deactivation (hydroxylation plus O-glucuronylation) of arteflene occur in the rat liver. The balance of these pathways is associated with cytotoxicity, although only at relatively high concentrations in the cultured hepatocyte. The hepatic metabolism may restrict the therapeutic effectiveness of arteflene because 8-hydroxyarteflene retains only about 25% of the parent drug s antimalarial activity, while the enone is inactive <2004173>. 

Drug activation by iron and heme may explain why endoperoxides are selectively toxic to malaria parasites. The malaria parasites live in a milieu of heme iron, which the parasite converts into insoluble hemozoin. Chloroquine, which binds heme, antagonizes the antimalarial activity of artemisinin. 

Several reports discuss the chemistry behind the antimalarial behaviour of artemisinins <04ACR397, 04AG(E)1381, 04JMC2945>. The important role of the peroxyketal unit in the antimalarial activity shown by endoperoxides derived from Eucalyptus grandis leaves has been recognised <04BMCL1433>. 

Bachi has extended this strategy to the synthesis of naturally occurring endoper-oxides with antimalarial activity via the thiol-oxygen cooxidation of dienes [47] (Scheme 8) the reaction involves the formation of a peroxy radical 4, which adds intramolecularly to the double bond to give the endoperoxide function required in the final product. 

---