Peroxidic
antimalarial agents including the sequiterpene artemisinins and the
synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction
of an endoperoxide bond. By chemically coupling this reduction to
release of a tethered drug species it is possible to confer two distinct
pharmacological effects in a parasite-selective fashion, both in vitro
and in vivo. Here we demonstrate the trioxolane-mediated delivery
of the antimalarial agent mefloquine in a mouse malaria model. Selective
partitioning of the trioxolane–mefloquine conjugate in parasitized
erythrocytes, combined with effective exclusion of the conjugate from
brain significantly reduced brain exposure as compared to mice directly
administered mefloquine. These studies suggest the potential of trioxolane-mediated
drug delivery to mitigate off-target effects of existing drugs, including
the adverse neuropsychiatric effects of mefloquine use in therapeutic
and chemoprophylactic settings
