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

Abstract

1-Deoxy- d -xylulose-5-phosphate reductoisomerase (DXR) in the nonmevalonate isoprene biosynthesis pathway is a target for developing 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 quantitative structure–activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized, and found to be highly potent inhibitors of P. falciparum DXR ( Pf DXR) having K i values of 1.9–13 nM, with the best one being ∼11× more active than fosmidomycin. These compounds also potently block the proliferation of multidrug resistant P. falciparum with EC 50 values as low as 170 nM. A 2.3 Å crystal structure of Pf DXR in complex with one of the inhibitors is reported, showing that the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and the Pf DXR account for the enhanced activity.