Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals
Language: 
English
Abstract: 

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 cells, 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 for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward 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 the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic 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.

Author(s): 
Fügi, Matthias A.
Wittlin, Sergio
Dong, Yuxiang
Vennerstrom, Jonathan L.
Item Type: 
Journal Article
Publication Title: 
Antimicrobial Agents and Chemotherapy
Journal Abbreviation: 
Antimicrob. Agents Chemother.
Publication Date: 
3/10/2015
Publication Year: 
2010
Pages: 
1042-1046
Volume: 
54
Issue: 
3
ISSN: 
1098-6596
DOI: 
10.1128/AAC.01305-09
Library Catalog: 
PubMed
Extra: 
PMID: 20028825 PMCID: PMC2825978

Turabian/Chicago Citation

Matthias A. Fügi, Sergio Wittlin, Yuxiang Dong and Jonathan L. Vennerstrom. 3/10/2015. "Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals." Antimicrobial Agents and Chemotherapy 54: 3: 1042-1046. 10.1128/AAC.01305-09.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/AAC.01305-09 | issn = 1098-6596 | volume = 54 | pages = 1042-1046 | last = Fügi | first = Matthias A. | coauthors = Wittlin, Sergio, Dong, Yuxiang, Vennerstrom, Jonathan L. | title = Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals | journal = Antimicrobial Agents and Chemotherapy | date = 3/10/2015 | pmid = | pmc = }} </ref>