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Heme alkylation by the antimalarial drug artemisinin is reported in vivo, within infected mice that have been treated at pharmacologically relevant doses. Adducts resulting from the alkylation of heme by the drug were characterized in the spleen of treated mice, and their glucuroconjugated derivatives were present in the urine. Because these heme--artemisinin adducts were not observed in noninfected mice, this report confirms that the alkylating activity of this antimalarial drug is related to the presence of the parasite in infected animals. The identification of heme--artemisinin adducts in mice should be considered as the signature of the alkylation capacity of artemisinin in vivo. alkylation | malaria | trioxane

Among potential new targets for antimalarial chemotherapy are Plasmodium falciparum cysteine proteases, known as falcipains. Falcipain-2 and falcipain-3 are food vacuole hemoglobinases that may have additional functions. The function of falcipain-1 remains uncertain. To better characterize the role of falcipain-1 in erythrocytic parasites, we disrupted the falcipain-1 gene and characterized recombinant parasites. Disruption of the falcipain-1 gene was confirmed with Southern blots, and loss of expression of falcipain-1 was confirmed with immunoblots and by loss of labeling with a specific protease inhibitor. Compared with wild-type parasites, falcipain-1 knockout parasites developed normally, with the same morphology, multiplication rate, and invasion efficiency, and without significant differences in sensitivity to cysteine protease inhibitors. In wild-type and knockout parasites, cysteine protease inhibitors blocked hemoglobin hydrolysis in trophozoites, with a subsequent block in rupture of erythrocytes by mature schizonts, but they did not inhibit erythrocyte invasion by merozoites. Our results indicate that although falcipain-1 is expressed by erythrocytic parasites, it is not essential for normal development during this stage or for erythrocyte invasion.

This article discusses the mechanism of action of artemisinin and synthesis of new antimalarial agents called 'trioxaquines'. The relationship of the alkylating ability of the endoperoxide-based artemisinin and heme related antimalarial efficacy is discussed. The synthesis of trioxaquines is carried out by covalent attachment of atrioxane residue with alkylating ability to a quinoline.

The manzamines have been identified as more effective antimalarial agents than the presently used drugs artemisinin and chloroquine. Neo-kauluamine has significant potential in antimalarial treatment.

The flexibility of the lactone methodology for the synthesis of axially chiral target biaryl molecules capable of accommodating any substitution pattern is presented. Research describes a synthetic strategy for the preparation of antimalarial korupensamines A and B and their anti-HIV dimers via a lactone precursor.

The results of a theoretical analysis of the reaction process of the intramolecular 1,5-hydrogen shift and the homolytic cleavage of the C-C bond for the model molecule of 6,7,8-trioxybicyclo[3,2,2]nonane are presented. A low activation free energy of 6.4 kcal/mol in the intramolecular 1,5-hydrogen shift process produces the first theoretical evidence for a low energy barrier.

Research has been conducted on the antimalarial drug arteflene containing peroxide. Results indicate that it generates an alkyl radical.

Results show that thiol-mediated reduction of ferric-protporphyrin IX yields ferrous-protoporphyrin IX, a heme polymerization inhibitor, which acts as an effective endogenous antimalarial compound.

Registration in Europe of several artemisinin drugs for the treatment of malaria can soon be expected. Artemisinin is isolated from the herb Artemisia annua, in use in China more than 2000 years as a herbal tea against fever. Artemisinin drugs are being used extensively in South-East Asia and increasingly in Africa. Active derivatives have been synthesized - artemether, arteether and artesunate - which are used for oral, intramuscular, rectal and intravenous administration. The origin, mechanism of action, efficacy and safety in patients, the pharmacokinetics and the position of this group of compounds among existing antimalarials are discussed in this review.

The cleavage reactions of qinghaosu (QHS), a novel sesquiterpene endoperoxide with potent malarial activity, and its analogues with Fe(II) catalyzed by FeSO4 in aqueous acetonitrile were investigated. Although the addition of a phosphate buffer slowed the cleavage reaction of QHS, no other changes were observed. Moreover, changing the amount of FeSO4 did not result to any observable changes and replacement of FeSO4 with FeCl3 did not produce any reaction at all.