Ruthenium Complexes of Atovaquone Acting on Multiple Stages of the Plasmodium Life Cycle

Here, we present the synthesis, characterization, and
pharmacological
evaluation of ruthenium complexes of broad-spectrum drug Atovaquone
(ATV). Structure–activity relationships revealed key determinants
for antiplasmodial activity, such as the importance of the oxidation
state [Ru(III) versus Ru(II)] and of hydrophilic
or lipophilic coligands. These complexes demonstrated broader activity
against both asexual and sexual parasite stages than ATV. Due to this
broader effect, complexes exhibited faster action in antiplasmodial
activity than ATV. Ruthenium content from the complexes’ treatment
gradually and selectively accumulates in the parasite cell milieu.
Efficacy was assessed in vivo against asexual and
sexual stages. Complexes were capable of blocking parasite transmission
from humans to insects, and this was achieved for both gametocytes
and oocyst stages, while ATV solely blocked oocysts. This is the first
example of metal complexes inhibiting both asexual and sexual parasites
with similar potency, broadly expanding the therapeutic utility of
metalladrugs in medicinal chemistry.