Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural diVerences within the active site between P. falciparum and human LDH, we have identiWed a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity proWle. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identiWcation of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.