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[摘要]：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 (PfDXR) having K-i values of 1.9-13 nM, with the best one being similar to 11x more active than fosmidomycin. These compounds also potently block the proliferation of multidrug resistant P. falciparum with EC50 values as low as 170 nM. A 2.3 angstrom crystal structure of PfDXR 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 PfDXR account for the enhanced activity. |
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