Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity.
These data suggest that iron(II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of animalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO(4)-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets.
Wang
Xiaofang
X
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, USA.
Creek
Darren J
DJ
Schiaffo
Charles E
CE
Dong
Yuxiang
Y
Chollet
Jacques
J
Scheurer
Christian
C
Wittlin
Sergio
S
Charman
Susan A
SA
Dussault
Patrick H
PH
Wood
James K
JK
Vennerstrom
Jonathan L
JL
D000478:Alkylation; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D006418:Heme / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000737:chemistry*
C503429:1,2,4-trioxane; D000962:Antimalarials; D005290:Ferric Compounds; D005296:Ferrous Compounds; D006571:Heterocyclic Compounds; D010545:Peroxides; C024823:ferric sulfate; D006418:Heme