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 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.