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.