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Molecular Pharmacology

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

Giancarlo A. Biagini, Nicholas Fisher, Neil Berry, Paul A. Stocks, Brigitte Meunier, Dominic P. Williams, Richard Bonar-Law, Patrick G. Bray, Andrew Owen, Paul M. O'Neill and Stephen A. Ward
Molecular Pharmacology May 2008, 73 (5) 1347-1355; DOI: https://doi.org/10.1124/mol.108.045120
Giancarlo A. Biagini
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.)
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Nicholas Fisher
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.)
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Neil Berry
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.)
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Paul A. Stocks
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.)
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Brigitte Meunier
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.)
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Dominic P. Williams
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.)
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Richard Bonar-Law
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.)
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Patrick G. Bray
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.)
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Andrew Owen
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.)
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Paul M. O'Neill
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.)
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Stephen A. Ward
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.)
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Abstract

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 Ki) 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 (Qo) of the bc1 complex. This is supported by favorable binding energies for in silico docking of dihydroacridinediones to P. falciparum bc1 Qo. Dihydroacridinediones represent an entirely new class of bc1 inhibitors and the potential of these compounds as novel antimalarial drugs is discussed.

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Molecular Pharmacology: 73 (5)
Molecular Pharmacology
Vol. 73, Issue 5
1 May 2008
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Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrial bc1 Complex

Giancarlo A. Biagini, Nicholas Fisher, Neil Berry, Paul A. Stocks, Brigitte Meunier, Dominic P. Williams, Richard Bonar-Law, Patrick G. Bray, Andrew Owen, Paul M. O'Neill and Stephen A. Ward
Molecular Pharmacology May 1, 2008, 73 (5) 1347-1355; DOI: https://doi.org/10.1124/mol.108.045120

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

Giancarlo A. Biagini, Nicholas Fisher, Neil Berry, Paul A. Stocks, Brigitte Meunier, Dominic P. Williams, Richard Bonar-Law, Patrick G. Bray, Andrew Owen, Paul M. O'Neill and Stephen A. Ward
Molecular Pharmacology May 1, 2008, 73 (5) 1347-1355; DOI: https://doi.org/10.1124/mol.108.045120
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