Malaria is the one of the deadliest
infectious diseases worldwide. Chemically,
quinolines are excellent
ligands for
metal coordination and are deployed as drugs for
malaria treatment. There is a growing body of evidence indicating that
metal complexes can be conjugated with
antimalarial quinolines to be used as chemical tools to overcome the disadvantages of
quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of
ruthenium(II)- and
gold(I)-containing
amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in
solution was investigated, demonstrating the stability of the
quinoline-
metal bond. RuII - and AuI -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the
metal-AQ complexes to reproduce the suppression of
heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that
metal coordination with
antimalarial quinolines is a potential chemical tool for
drug design and discovery in
malaria and other
infectious diseases susceptible to
quinoline treatment.