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

Abstract

1-Deoxy-<i>D</i>-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against <i>P. falciparum</i> malaria in clinical trials. Based on 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 <i>P. falciparum</i> DXR (<i>Pf</i>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 multi-drug resistant <i>P. falciparum</i> with EC₅₀ values as low as 170 nM. A 2.3 Å crystal structure of <i>Pf</i>DXR in complex with one of the inhibitors is reported, showing 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 <i>Pf</i>DXR account for the enhanced activity.