THESIS
2010
viii, 156 p. : ill., map ; 30 cm
Abstract
Artemisinin is a sesquiterpene lactone peroxide that possesses potent anti-malarial
activity. 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 dihydroartemi...[
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Artemisinin is a sesquiterpene lactone peroxide that possesses potent anti-malarial
activity. 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.
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