Further optimization of plakortin pharmacophore: Structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity

For the optimization of the plakortin pharmacophore, we recently proposed a straightforward synthesis of 4-carbomethoxy-3-methoxy-1,2-dioxanes as potential antimalarial drug candidates. Herein we report the chemoselective reduction of the 4-carbomethoxy group which has allowed us to prepare in good yields twenty-four new endoperoxides carrying either the hydroxymethyl or the methoxymethyl group on C4 in various stereochemical arrangements with respect to the alkyl groups on C3 and C6 (the endoperoxide carbons). Some of these compounds showed promising in vitro antimalarial activities, both against chloroquine-resistant (CQ-R) and susceptible (CQ-S) strains of Plasmodium falciparum, with IC50 values in the range of 0.5-1.0 mu M. Compound 8g showed activity against the CQ-R strain comparable to that of the structurally more demanding plakortin.