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Accelerated Communication

Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrial bc₁ Complex

Liverpool School of Tropical Medicine, Liverpool, United Kingdom (G.A.B., N.F., P.A.S., P.G.B., S.A.W.). Departments of Chemistry (N.B., R.B.-L., P.M.O.) and Pharmacology and Therapeutics (D.P.W., A.O.), University of Liverpool, Liverpool, United Kingdom; and Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France (B.M.)

The development of drug resistance to affordable drugs has contributed to a global increase in the number of deaths from malaria. This unacceptable situation has stimulated research for new drugs active against multidrug-resistant Plasmodium falciparum parasites. In this regard, we show here that deshydroxy-1-imino derivatives of acridine (i.e., dihydroacridinediones) are selective antimalarial drugs acting as potent (nanomolar K_i) inhibitors of parasite mitochondrial bc₁ complex. Inhibition of the bc₁ complex led to a collapse of the mitochondrial membrane potential, resulting in cell death (IC₅₀ 15 nM). The selectivity of one of the dihydroacridinediones against the parasite enzyme was some 5000-fold higher than for the human bc₁ complex, significantly higher (200 fold) than that observed with atovaquone, a licensed bc₁-specific antimalarial drug. Experiments performed with yeast manifesting mutations in the bc₁ complex reveal that binding is directed to the quinol oxidation site (Q_o) of the bc₁ complex. This is supported by favorable binding energies for in silico docking of dihydroacridinediones to P. falciparum bc₁ Q_o. Dihydroacridinediones represent an entirely new class of bc₁ inhibitors and the potential of these compounds as novel antimalarial drugs is discussed.

Address correspondence to: Giancarlo A. Biagini, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. E-mail: biagini{at}liv.ac.uk

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