Antimalarial and Structural Studies of Pyridine-Containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase

d-xylulose-5-phosphate reductoisomerase(DXR)in the nonmevalonate isoprene biosynthesis pathway is a target fordeveloping antimalarial drugs. Fosmidomycin, a potent DXR inhibitor,showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. On the basis of our previous quantitativestructure–activity relationship (QSAR) and crystallographicstudies, several novel pyridine-containing fosmidomycin derivativeswere designed, synthesized, and found to be highly potent inhibitorsof P. falciparum DXR (PfDXR) having K_i values of 1.9–13 nM, with the bestone being ∼11× more active than fosmidomycin. These compoundsalso potently block the proliferation of multidrug resistant P. falciparum with EC₅₀ values as low as 170nM. A 2.3 Å crystal structure of PfDXR in complexwith one of the inhibitors is reported, showing that the flexibleloop of the protein undergoes conformational changes upon ligand bindingand a hydrogen bond and favorable hydrophobic interactions betweenthe pyridine group and the PfDXR account for theenhanced activity.