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Publication Abstract from PubMed

1-Deoxy-D-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 P. falciparum 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 P. falciparum DXR (PfDXR) having Ki values of 1.9 - 13 nM, with the best one being ~11x more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant P. falciparum with EC50 values as low as 170 nM. A 2.3 A crystal structure of PfDXR 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 PfDXR account for the enhanced activity.

Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.,Xue J, Diao J, Cai G, Deng L, Zheng B, Yao Y, Song Y ACS Med Chem Lett. 2013 Feb 14;4(2):278-282. PMID:23795240^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.