Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials
Language: 
English
Abstract: 

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

Author(s): 
Creek, Darren J.
Charman, William N.
Chiu, Francis C. K.
Prankerd, Richard J.
Dong, Yuxiang
Vennerstrom, Jonathan L.
Charman, Susan A.
Item Type: 
Journal Article
Publication Title: 
Antimicrobial Agents and Chemotherapy
Journal Abbreviation: 
Antimicrob. Agents Chemother.
Publication Date: 
4/8/2015
Publication Year: 
2008
Pages: 
1291-1296
Volume: 
52
Issue: 
4
ISSN: 
0066-4804
DOI: 
10.1128/AAC.01033-07
Library Catalog: 
PubMed
Extra: 
PMID: 18268087 PMCID: PMC2292547

Turabian/Chicago Citation

Darren J. Creek, William N. Charman, Francis C. K. Chiu, Richard J. Prankerd, Yuxiang Dong, Jonathan L. Vennerstrom and Susan A. Charman. 4/8/2015. "Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials." Antimicrobial Agents and Chemotherapy 52: 4: 1291-1296. 10.1128/AAC.01033-07.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/AAC.01033-07 | issn = 0066-4804 | volume = 52 | pages = 1291-1296 | last = Creek | first = Darren J. | coauthors = Charman, William N., Chiu, Francis C. K., Prankerd, Richard J., Dong, Yuxiang, Vennerstrom, Jonathan L., Charman, Susan A. | title = Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials | journal = Antimicrobial Agents and Chemotherapy | date = 4/8/2015 | pmid = | pmc = }} </ref>