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

High Resolution Image Download MS PowerPoint Slide 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.