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J. Biol. Chem., Vol. 279, Issue 30, 31429-31439, July 23, 2004

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Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity^*

Angus Cameron, Jon Read, Rebecca Tranter, Victoria J. Winter, Richard B. Sessions, R. Leo Brady¶, Livia Vivas||, Anna Easton||, Howard Kendrick||, Simon L. Croft||, David Barros**, Jose Luis Lavandera**, José Julio Martin**, Felix Risco**, Silvestre García-Ochoa**, Fracisco Javier Gamo**, Laura Sanz**, Luisa Leon**, Jose R. Ruiz**, Raquel Gabarró**, Araceli Mallo**, and Federico Gómez de las Heras**

From the Department of Biochemistry and Molecular Recognition Centre, University of Bristol, Bristol BS8 1TD, ^||London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom, and ^**GlaxoSmithKline, Parque Tecnológico de Madrid, Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD⁺ regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD⁺ cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.

Received for publication, March 3, 2004 , and in revised form, April 22, 2004.

^* This work was in part supported by a grant from the Medicines for Malaria Venture (Geneva, Switzerland). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains additional text and Tables S1A–S1D.

The atomic coordinates and structure factors (codes 1T24, 1T25, 1T26, 1T2C, 1T2D, 1T2E, and 1T2F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Supported by a studentship from the Biotechnology and Biological Sciences Research Council (BBSRC), United Kingdom.

^¶ To whom correspondence should be addressed. Tel.: 44-117-928-7436; Fax: 44-117-928-8274; E-mail: L.Brady{at}bris.ac.uk.

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