%0 Journal Article %A Deng, Lisheng %A Diao, Jiasheng %A Chen, Pinhong %A Pujari, Venugopal %A Yao, Yuan %A Cheng, Gang %A Crick, Dean C. %A V. Venkataram Prasad, B. %A Song, Yongcheng %D 2011 %T Inhibition of 1-Deoxy-d-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR, and Crystallographic Studies %U https://acs.figshare.com/articles/journal_contribution/Inhibition_of_1_Deoxy_d_Xylulose_5_Phosphate_Reductoisomerase_by_Lipophilic_Phosphonates_SAR_QSAR_and_Crystallographic_Studies/2630718 %R 10.1021/jm200363d.s001 %2 https://acs.figshare.com/ndownloader/files/4281814 %K MtDXR %K QSAR %K SAR %K DXR inhibitors %K 48 EcDXR inhibitors %X 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 E. coli DXR (EcDXR) with a Ki of 420 nM. Structure–activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR: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. %I ACS Publications