title: Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Recognition Centre, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Angus
authors.initials: A
authors.lastname: Cameron
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tranter
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Winter
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sessions
authors.forename: R Leo
authors.initials: RL
authors.lastname: Brady
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Anna
authors.initials: A
authors.lastname: Easton
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Lavandera
authors.forename: José Julio
authors.initials: JJ
authors.lastname: Martin
authors.forename: Felix
authors.initials: F
authors.lastname: Risco
authors.forename: Silvestre
authors.initials: S
authors.lastname: García-Ochoa
authors.forename: Fracisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Laura
authors.initials: L
authors.lastname: Sanz
authors.forename: Luisa
authors.initials: L
authors.lastname: Leon
authors.forename: Jose R
authors.initials: JR
authors.lastname: Ruiz
authors.forename: Raquel
authors.initials: R
authors.lastname: Gabarró
authors.forename: Araceli
authors.initials: A
authors.lastname: Mallo
authors.forename: Federico
authors.initials: F
authors.lastname: Gómez de las Heras
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001393:Azoles; D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase