Novel Endochin-Like Quinolones Exhibit Potent Activity against Plasmodium knowlesi but Do Not Synergize with Proguanil.

Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active and in animal models. While these quinolones exhibit potent activity against and , their activity against the zoonotic agent is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against and compared this with their activity against tested under identical conditions. We demonstrated that ELQs are potent against (50% effective concentration, <117 nM) and equally effective against We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against than , while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against However, against , no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species.