title: Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials.
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.
authors.affiliation: Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Prankerd
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000478:Alkylation; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D013141:Spiro Compounds; D006418:Heme; C031327:artemisinin