Arteflene antimalarial

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. 

Bicyclic endoperoxide antimalarials, such as arteflene (5) and naturally occurring ying-zhaosu A (7) and endoperoxide 8, share a unique feature of this class of compounds in their peroxide bond. As mentioned earlier, the peroxide bond of artemisinin has... 

O Neill and coworkers were also able to spin-trap the previously proposed C-centred radical 63b with sodium 3,5-dibromo-4-nitrosobenzenesulphonate (DBNBS) and the EPR of the adduct 64b was characteristic of a secondary radical (Scheme 19B). It was suggested that the parasiticidal action of arteflene stems from the alkylating properties of the radical intermediate or possibly from the enone 63a, which may be able to react with intracellular nucleophiles by a Michael addition. The enone itself did not exhibit antimalarial activity, possibly due to extracellular detoxification by glntathione before reaching its intraparasitic site of action. 

Meunier and coworkers investigated the degradation of arteflene using manganese(II) TPP as a heme model. They were able to spin-trap the secondary C-centred radical with the piperidyl radical (TEMPO) and the adduct 64c was fully characterized following acetylation of the crude reaction mixture (Scheme 20). An arteflene-heme adduct was not observed and the authors suggest that this is attributable to steric hindrance factors. However, this could be further evidence that endoperoxide antimalarials do not target heme. 

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. 

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>. 

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