1.2.4- Trioxane antimalarials endoperoxides

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

This pro-drug approach provides a paradigm for future antimalarial drug discovery efforts in the sense that this approach can be extended to any protease inhibitor that contains a carbonyl group as the reactive protease inhibitor warhead . Simply masking the carbonyl group within a trioxane or endoperoxide provides a unique and selective mechanism for targeting the malaria parasite by two different mechanisms . ... 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345 00JCS(P1)1265 00JMC2753 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 

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. ... 

Endoperoxides derived from the cycloaddition of singlet oxygen to butadienes are readily converted into the epoxides. The epoxy oxygen is close to the peroxide unit, resembling the trioxane moiety of artemisinin and the epoxides show antimalarial aetivity (Scheme 25) <04JMC1833>. 

Endoperoxides (also 1,2-dioxetanes) are versatile starting materials for further transformations. In view of the weak 0-0 bond, these peroxides are thermally sensitive to homolytic cleavage, a feature that makes most of them ha2aidous. Ring opening opens up attractive opportunities for selective transformations that include reductions (diols), oxidations (dicarbonyl products), rearrangements (hydroxy carbonyl compounds, epoxy carbonyl compounds, fo/s-epoxides, ene diones, etc.) and additions (polycycKc dioxanes or trioxanes, some of which display antimalarial activity). The synthesis and the subsequent reactions of the 2,3-dioxabicyclo[2.2.2]oct-7-en-5-one skeleton have been studied by Adam etak An impressive number of chemical transformations and examples for applications in organic synthesis have been collected in several reviews. 

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