Related Articles Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) With Non-peroxidic Isosteres and Nitroxyl Radicals.

Antimicrob Agents Chemother. 2009 Dec 22;

Authors: Fügi MA, Wittlin S, Dong Y, Vennerstrom JL

Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed in combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that formation of carbon-centered radicals is critical to the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend towards greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions resulting in a lower proportion of radicals available for subsequent chemical reactions such as alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their non-peroxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets.

PMID: 20028825 [PubMed - as supplied by publisher]