Received for publication January 10, 2008.
Revised February 29, 2008.
Accepted for publication February 29, 2008.

ACRIDINEDIONES: SELECTIVE AND POTENT INHIBITORS OF THE MALARIA PARASITE MITOCHONDRIAL bc₁ COMPLEX

Abstract

Clinical treatment-failures to affordable drugs have contributed to a global increase in the number of deaths arising from malaria infection. This unacceptable situation has stimulated research for new drugs active against multi-drug resistant Plasmodium falciparum parasites. In this regard, here we show that deshydroxy-1-imino derivatives of acridine (i.e. dihydroacridinediones) are selective antimalarials acting as potent (nM K_i) inhibitors of parasite mitochondrial bc₁ complex. Inhibition of the bc₁ complex lead to a collapse of the mitochondrion membrane potential (_m) resulting in cell death (IC₅₀ ~15nM). 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 containing 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 favourable 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 antimalarials is discussed.

Key words: Structure-activity relationships and modeling, Thermodynamic and kinetic processes and modeling, Fluorescence techniques, Mitochondrial toxins, Protein targets, Antifungal drugs, Antiprotozoal drugs