Iron-mediated degradation kinetics of substituted dispiro-1,2,4-trioxolane antimalarials.
The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalarial activity.
Creek
Darren J
DJ
Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Charman
William N
WN
Chiu
Francis C K
FC
Prankerd
Richard J
RJ
McCullough
Kevin J
KJ
Dong
Yuxiang
Y
Vennerstrom
Jonathan L
JL
Charman
Susan A
SA
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology
D000962:Antimalarials; D003510:Cyclohexanes; D005296:Ferrous Compounds; D006573:Heterocyclic Compounds, 1-Ring; D013141:Spiro Compounds; D000218:Adamantane