Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex.
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 bc(1) complex. Inhibition of the bc(1) complex led to a collapse of the mitochondrial membrane potential, resulting in cell death (IC(50) approximately 15 nM). The selectivity of one of the dihydroacridinediones against the parasite enzyme was some 5000-fold higher than for the human bc(1) complex, significantly higher ( approximately 200 fold) than that observed with atovaquone, a licensed bc(1)-specific antimalarial drug. Experiments performed with yeast manifesting mutations in the bc(1) complex reveal that binding is directed to the quinol oxidation site (Q(o)) of the bc(1) complex. This is supported by favorable binding energies for in silico docking of dihydroacridinediones to P. falciparum bc(1) Q(o). Dihydroacridinediones represent an entirely new class of bc(1) inhibitors and the potential of these compounds as novel antimalarial drugs is discussed.
Biagini
Giancarlo A
GA
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. biagini@liv.ac.uk
Fisher
Nicholas
N
Berry
Neil
N
Stocks
Paul A
PA
Meunier
Brigitte
B
Williams
Dominic P
DP
Bonar-Law
Richard
R
Bray
Patrick G
PG
Owen
Andrew
A
O'Neill
Paul M
PM
Ward
Stephen A
SA
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology; D002417:Cattle; D004357:Drug Synergism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D010084:Oxidation-Reduction / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism
D000166:Acridines; D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D006418:Heme; D014450:Electron Transport Complex III; D053626:Atovaquone