Examination of Coligands in Mefloquine–Metal Complexes Reveals the Structural Determinants of Activity against Plasmodium falciparum and Schistosoma mansoni

Mefloquine (MQ) is
an important component for antiparasitic
therapy.
Herein, the synthesis and antiplasmodial and antischistosomal activities
of MQ–metal complexes of the general formula [M(II)(L)(MQ)]PF6 are described. Variation of the metal center (platinum and
palladium) and coligand (phosphine or bipyridine) consistently yielded
MQ coordinated as a N,O-bidentate
ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal
center augmented the antiparasitic property of MQ by functioning as
a thioredoxin/glutathione reductase-targeting moiety, while the coligand
modulated chemical reactivity and physicochemical properties. MQ–Pt
complexes displayed high in vivo efficacy. The intracellular
accumulation of the metal in parasite cells contributed to the abrogation
of essential biochemical pathways. Notably, despite being isostructural,
Pd complexes differed from their Pt counterparts in their ligand dissociation
behavior. The current work establishes a new structural framework
for developing metal-based antiparasitic agents capable of selectively
targeting essential parasite biochemical pathways while sparing mammalian
cells.