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Acridinediones: Selective and potent inhibitors of the malaria parasite mitochondrial bc(1) complex

Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Fisher, Nicholas, Berry, N., Stocks, Paul A., Meunier, B., Williams, D. P., Bonar-Law, R., Bray, Patrick, Owen, A., O'Neill, P. M. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2008) 'Acridinediones: Selective and potent inhibitors of the malaria parasite mitochondrial bc(1) complex'. Molecular Pharmacology, Vol 73, Issue 5, pp. 1347-1355.

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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 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 (IC50 similar to 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 (similar to 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.

Item Type: Article
Uncontrolled Keywords: blood schizontocidal action plasmodium-falciparum cytochrome-b antimalarial-drugs ferriprotoporphyrin-ix hematin polymerization atovaquone resistance respiratory-chain binding-site mutations
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1124/mol.108.045120
Depositing User: Mary Creegan
Date Deposited: 12 Aug 2010 16:02
Last Modified: 06 Feb 2018 13:00
URI: http://archive.lstmed.ac.uk/id/eprint/735

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