Targeting the Cytochrome bc 1 Complex of Leishmania Parasites for Discovery of Novel Drugs

Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochromebc 1 fromPlasmodium falciparum andToxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain ofLeishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes ofLeishmania mexicana andL. donovani , with 50% inhibitory concentrations (IC50 s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochromebc 1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.