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A chemical model for mode of antimalarial action of artemisinin

Authors Pai, Hendry Hung On
Issue Date 1998
Summary Artemisinin 8, an active component in a traditional Chinese herb called qinghao, has been extensively used to treat severe malaria. However, mode of action of artemisinin 8 and derivatives is still not clear. Current proposals state that the drug potency is due to following species: the secondary C-4 radical species 58, the Fe(IV)=0 species 41 and epoxide 59, and the adduct formed between hemin and artemisinin 8. In light of the limitations to these current models, a different model has proposed in this thesis. In the specific case of artemisinin 8, unzipping of the tetracyclic ring by a nucleophile is proposed to generate free hydroperoxide 87. In the case of dihydroartemisinin 9, ring opening is effected by a base which abstracts the hydroxyl proton. The open hydroperoxide intermediate 87 is proposed to give hydroxyl and alkoxy radicals, or act as a source of electrophilic oxygen which can damage biomolecules in the malarial parasites. The presence of the hydroperoxide 87 was proved by using tertiary amines 122 to intercept the hydroperoxide oxygen atom to give the corresponding N-oxides 124. In the case of artemisinin 8, it is found that the ultimate deoxy products resulting from reduction of the hydroperoxide depended upon how the reaction mixture was worked up. In the case of dihydroartemisinin 9, although its ring opening is believed to be more facile than artemisinin 8, the generation of N-oxide 124 was found to be less significant, whereas formation of deoxyartemisinin 29 was prominent. The reasons for this may be due to the inability of the tertiary amine to effectively intercept the opened hydroperoxide. The solution of this problem may rely on the use of a suitable Lewis acid which can selectively complex with the peroxide linkage and thus facilitate the ring opening process. Future work will be focused on this aspect.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 1998
Language English
Format Thesis
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