Kinetics of iron-mediated artemisinin degradation: effect of solvent composition and iron salt.
The antimalarial endoperoxides, such as artemisinin, are postulated to exert their potent parasiticidal activity via the formation of reactive intermediates in the iron-rich infected erythrocyte. The in vitro chemical reaction profile of putative endoperoxide antimalarials and ferrous iron is often qualitatively used to assess their potential antimalarial activity and to develop a structure-reactivity relationship. This study utilized LCMS to monitor the kinetics of artemisinin degradation and product formation in the presence of iron. A second order degradation reaction (k = 18 M(-1) h(-1)) was observed from the reaction of artemisinin with ferrous sulphate in aqueous acetonitrile to produce a number of stable isomeric rearrangement products. A systematic study of the effect of a number of solvent systems and different iron salts showed pronounced changes in reaction rate and product distribution. The significant effects observed in the current study highlight the need to carefully control reaction conditions when studying peroxide antimalarial stability or attempting to develop in vitro/in vivo correlations of endoperoxide antimalarials and their reactivity with iron.
Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Darren J
DJ
Creek
Francis C K
FC
Chiu
Richard J
RJ
Prankerd
Susan A
SA
Charman
William N
WN
Charman
D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry*; D004355:Drug Stability; D005296:Ferrous Compounds / Q000737:chemistry*; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D013058:Mass Spectrometry; D012717:Sesquiterpenes / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013997:Time Factors
D000962:Antimalarials; D037621:Artemisinins; D005296:Ferrous Compounds; D012717:Sesquiterpenes; D012997:Solvents; C020748:ferrous sulfate; C060433:3-hydroxydeoxyartemisinin; C031327:artemisinin; D007501:Iron; C011819:ferrous gluconate