Inhibition of 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR, and Crystallographic Studies

1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against <i>E. coli</i> DXR (<i>Ec</i>DXR) with a <i>K</i><sub>i</sub> of 420 nM. Structure–activity relationships (SAR) are discussed, which can be rationalized using our <i>Ec</i>DXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from <i>Mycobacterium tuberculosis</i> (<i>Mt</i>DXR) have not been performed well, 48 <i>Ec</i>DXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against <i>Mt</i>DXR. The crystal structure of a <i>Mt</i>DXR:inhibitor complex reveals the flexible loop containing the residues 198–208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.