| Malaria is a major public health problem in underdeveloped countries and is responsible for over 100 million clinical cases and 1 to 2 million deaths each year. Drug resistance is a very serious problem and more effective antimalarial drugs are needed urgently. In this thesis, two new drugs, daphnetin and artemisinin (qinghaosu) were studied.; Daphnetin is a dihydroxycoumarin which is being used in China for the treatment of coagulation disorders. It is also a chelator and an antioxidant. In vitro, daphnetin has moderate antimalarial activity while several related compounds, such as scopoletin, 2,3-dihydroxybenzoic acid (2,3-DHB) and 3,4-dihydroxybenzoic acid (3,4-DHB) are inactive. Daphnetin does not appear to be an oxidant drug, since it does not spontaneously generate superoxide in vitro. However, it does alkylate bovine serum albumin (BSA) when incubated in the presence of iron.; Artemisinin (qinghaosu) and its derivatives represent a promising new class of antimalarial drugs. In vitro, artemisinin, particularly in the presence of hemin, has a potent oxidant effect on red cell membranes causing the oxidation of protein thiols and the formation of high-molecular weight protein aggregates. Thiol oxidation can be prevented by an iron chelator deferoxamine (desferrioxamine, DFO) or {dollar}alpha{dollar}-tocopherol, an antioxidant. Therefore, artemisinin acts as an oxidant.; Artemisinin alkylates various proteins including red cell membrane proteins, human serum albumin (HSA), and some hemoproteins in vitro. The results of electrospray ionization mass spectra (ESI-MS) showed that the drug modified-HSA is 478 dalton bigger than HSA. Binding between artemisinin and albumin probably involves thiol and amino groups via both iron-dependent and iron-independent reactions. Artemisinin also binds to hemoproteins on the protein moiety rather than the heme. In addition, dihydroartemisinin binds to HSA whereas deoxyartemisinin, an inactive derivative, does not. Furthermore, artemisinin appears to associate with hemozoin in P. falciparum infected red cells.; In summary, both daphnetin and artemisinin alkylate proteins. Iron appears to catalyze the alkylations. Artemisinin is also an oxidant drug while daphnetin is not. Therefore, drug alkylation plays a very important role in the mode of action of these antimalarial drugs. |
