Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane

We describe the first
systematic study of antimalarial 1,2,4-trioxolanes
bearing a substitution pattern regioisomeric to that of arterolane.
Conformational analysis suggested that trans-3″-substituted
trioxolanes would exhibit Fe­(II) reactivity and antiparasitic activity
similar to that achieved with canonical cis-4″
substitution. The chiral 3″ analogues were prepared as single
stereoisomers and evaluated alongside their 4″ congeners against
cultured malaria parasites and in a murine malaria model. As predicted,
the trans-3″ analogues exhibited in vitro
antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for
some of the congeneric pairs. The best of the novel 3″ analogues
(e.g., 12i) outperformed arterolane itself, producing
cures in mice after a single oral exposure. Overall, this study suggests
new avenues for modulating Fe­(II) reactivity and the pharmacokinetic
and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.