Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (Dxr): A Review of the Synthesis and Biological Evaluation of Recent Inhibitors

Emily      R. Jackson; Cynthia      S. Dowd

Abstract

Isoprene biosynthesis is an essential component of metabolism. Two pathways are known for the production of five-carbon (isoprene) intermediates: the mevalonate and nonmevalonate pathways. As many pathogenic organisms rely exclusively on the nonmevalonate pathway (NMP) for isoprenoids and humans do not, the enzymes of this route have been recently explored as new therapeutic targets. The second and first-committed step in the NMP is catalyzed by 1-deoxy-Dxylulose- 5-phosphate reductoisomerase (Dxr) and has received significant attention as a novel drug target. This review describes the biochemistry and crystal structures of Dxr and the synthesis and biological activity of inhibitors to date, with a focus on compounds targeting E. coli, Plasmodium, and M. tuberculosis enzymes and intact cells. Most inhibitors for Dxr use natural products fosmidomycin and FR900098 as starting points. The review discusses several families of fosmidomycinrelated analogs including α-substituted, ‘reverse’ and modified hydroxamate, spacer-modified, and hydroxy-amide analogs. Also discussed are non-fosmidomycin-like inhibitors, the aryl phosphonates, and lipophilic prodrugs of fosmidomycin and FR900098 designed to increase cell penetration. A comprehensive SAR of inhibitors is presented.

Keywords: Dxr, fosmidomycin, nonmevalonate pathway, isoprene, tuberculosis, malaria, therapeutic targets, aryl phosphonates, hydroxy-amide analogs, cell penetration, drug-resistant organisms, steroid hormones, human homologs, Isoprenoids