Abstract
The emergence of multi-drug resistant tuberculosis, coupled with the increasing overlap of the AIDS and tuberculosis pandemics has brought tuberculosis to the forefront as a major worldwide health concern. In an attempt to find new inhibitors of the enzymes in the essential rhamnose biosynthetic pathway, a virtual library of 2,3,5 trisubstituted-4-thiazolidinones was created. These compounds were then docked into the active site cavity of 6'hydroxyl; dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase (RmlC) from Mycobacterium tuberculosis. The resulting docked conformations were consensus scored and the top 5% were slated for synthesis. Thus far, 94 compounds have been successfully synthesized and initially tested. Of those, 30 (32%) have > or =50% inhibitory activity (at 20 microM) in the coupled rhamnose synthetic assay with seven of the 30 also having modest activity against whole-cell M. tuberculosis.
Original language | English |
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Pages (from-to) | 3227-3230 |
Number of pages | 4 |
Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 13 |
Issue number | 19 |
Early online date | 9 Aug 2003 |
DOIs | |
Publication status | Published - 16 Oct 2003 |
Keywords
- Binding Sites
- Drug Delivery Systems
- Hexosyltransferases
- Mycobacterium tuberculosis
- Rhamnose
- Thiazolidinediones