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

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 <i>N</i>,<i>O</i>-bidentate ligand. Biological evaluation against <i>Plasmodium falciparum</i> and <i>Schistosoma mansoni</i> 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 <i>in vivo</i> 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.