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Antimicrobial Agents and Chemotherapy, April 2008, p. 1291-1296, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01033-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials{triangledown}

Darren J. Creek,1 William N. Charman,1 Francis C. K. Chiu,1 Richard J. Prankerd,1 Yuxiang Dong,2 Jonathan L. Vennerstrom,2 and Susan A. Charman1*

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia,1 College of Pharmacy, University of Nebraska Medical Centre, Omaha, Nebraska 681982

Received 7 August 2007/ Returned for modification 16 November 2007/ Accepted 30 January 2008

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.

* Corresponding author. Mailing address: Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Phone: 61 3 9903 9626. Fax: 61 3 9903 9560. E-mail: susan.charman{at}vcp.monash.edu.au

{triangledown} Published ahead of print on 11 February 2008.

Antimicrobial Agents and Chemotherapy, April 2008, p. 1291-1296, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01033-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Creek, D. J., Ryan, E., Charman, W. N., Chiu, F. C. K., Prankerd, R. J., Vennerstrom, J. L., Charman, S. A. (2009). Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin. Antimicrob. Agents Chemother. 53: 3496-3500 [Abstract] [Full Text]  


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