AI Article Synopsis
- The conversion of DOXP to MEP is effectively inhibited by Dxr inhibitors like fosmidomycin, which is a natural antibiotic.
- To predict how closely related compounds bind to Dxr, researchers are synthesizing various fosmidomycin derivatives to improve target affinity.
- They have created a range of phosphonic acids that show inhibitory activity against E. coli and P. falciparum Dxr, with IC(50) values varying between 1 to over 30 microM.
Article Abstract
The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported.
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| http://dx.doi.org/10.1002/cbdv.200890060 | DOI Listing |
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