Preparation of polar artemisinins for cerebral malaria and model mechanistic studies

Artemisinin is a sesquiterpene lactone peroxide that possesses potent anti-malarialactivity. It is isolated from a plant that has been used since ancient times in China for treatment of fevers and chills. Its importance is evident in the use of current malaria treatment that employs artemisinin combination therapy (ACT) in which the advantages of potency of artemisinin and long half-life quininoline antimalarial drugs are combined. Cerebral malaria or severe and complicated malaria renders the patient comatose, such that drug administrated in an oral way is impossible. Only the water-soluble artesunate of the current known artemisinins can be administrated to the patient intravenously. However, it is very unstable, and undergoes rapid hydrolysis to the neutrotoxic dihydroartemisinin (DHA) in vivo. It is necessary to prepare a potent, inert, water-soluble and cheap artemisinin for the cerebral malaria patients. In the first part of this thesis, four series of polar artemisinin derivatives were prepared. They display better anti-malarial activity than artesunate. Artemisone is a very potent anti-malarial compound which is being developed for new Phase II trials. It has been reported that decomposition occurs by protonation at nitrogen atom followed by elimination when artemisone is in an acidic medium. To avoid the decomposition, and to evaluate a structure-activity relationship, attempts were made to prepare an artemisone homologue in which a methylene group is inserted between nitrogen atom and C-10 from DHA. With the additional methylene group, the compound should be less vulnerable to the decomposition. The synthetic pathway to the homologue will be discussed. Although artemisinin derivatives have been used as anti-malarial drugs, their mode of action is still not understood. The concept that artemisinin acts as a reactive oxygen species (ROS) source which upsets the parasites’ redox balance system is not widely accepted. However, artemisinins may also interfere with redox active cofactors of enzymes that maintain redox balance within the parasite. It has been shown in our group that artemisinins oxidize reduced flavins generated in situ from the flavin and NADPH. In the final part of the thesis, an examination of the relative rates of decomposition of various epimeric artemisinins with riboflavin and the NADPH model compound N-benzyl-1,4-dihydronicotinamide were carried out in order to establish if there is a correlation between decomposition rate, the anti-malaria activity and the stereochemistry of substituents near the peroxide bridge