Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarilas with heme has been investigated to provide further insight into the mechanism of action for this importnat 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-meidated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R squared=0.88) was found between the extent of heme alkylation and in vitro antimalrial activity. Significanlty less heme alkylation was observed for the clinically utilized artemisinin derivatives compared tot he equipotent trioxolanes included in this study.