PT  - JOURNAL ARTICLE
AU  - Giancarlo A. Biagini
AU  - Nicholas Fisher
AU  - Neil Berry
AU  - Paul A. Stocks
AU  - Brigitte Meunier
AU  - Dominic P. Williams
AU  - Richard Bonar-Law
AU  - Patrick G. Bray
AU  - Andrew Owen
AU  - Paul M. O'Neill
AU  - Stephen A. Ward
TI  - Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrial <em>bc</em><sub>1</sub> Complex
AID  - 10.1124/mol.108.045120
DP  - 2008 May 01
TA  - Molecular Pharmacology
PG  - 1347--1355
VI  - 73
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/73/5/1347.short
4100  - http://molpharm.aspetjournals.org/content/73/5/1347.full
SO  - Mol Pharmacol2008 May 01; 73
AB  - 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.