Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals

• DOI: 10.1128/aac.01305-09
• Publication Date: 2009-12-23T02:10:19Z
• Authors: Matthias A. Fügi; Sergio Wittlin; Yuxiang Dong; Jonathan L. Venne...
• Keywords: Peroxide; Hemozoin

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