Antimalarial drugs, degradation

Famin, O. Krugliak, M. Ginsburg, H. Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs. Biochem. Pharmacol, 1999, 58(1) 59-68. 

Otherwise, interest continues in the artemisinins the degradation of artemisinin 17 itself, and of a number of analogs and their reaction with various reagents, has been studied carefully. In order to find potential antimalarial drugs (artemisinin 17 itself is limited by its low solubility and poor oral bioavailibility), some interesting reactions have been reported and characteristic examples are now presented. 

These results show that, in principle, it is possible to prolong the duration of action of certain antimalarial drugs by inhibiting their enzymatic degradation. However, to be of practical consequence, the enzyme inhibitor or extender must be as persistent as the antimalarial itself, or must cause a persistent change in the metabolism of the antimalarial further, both drug and extender must exhibit much more protracted action than known substances. 

Of the parasitic diseases the most devastating one is malaria with a worldwide death toll of more than a million people. It is transmitted by the mosquito. To combat this, the life cycle and metabolism of the parasite Plasmodium falciparum is affected through a reduction in the synthesis of xanthurenic acid (92). Xanthurenic acid, required for gametogenesis and fertility of the parasite, is synthesized in the tryptophan degradation pathway through the PLP-dependent enzyme kynurenine aminotransferase. Hence, this enzyme is a target for the development of antimalarial drugs. 

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. 

Photodegradation studies have been carried out for several antimalarial compounds (Kristensen et al., 1993 Nord et al., 1991 Tpnnesen et al., 1988 Tpnnesen and Grislingaas, 1990). The main degradation products of chloroquine and hydroxychloroquine correspond to their in vivo metabolites. These degradation products are also demonstrated to be photolabile (unpublished results). Some of the photodegradation products of hydroxychloroquine seem to be more potent as photosensitizers than the parent drug (Kristensen et al., 1994a). 

---