Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis

Babaoglu, Kerim, Page, Mark A, Jones, Victoria C, McNeil, Michael R, Dong, Changjiang, Naismith, James H and Lee, Richard E (2003) Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis. Bioorganic & Medicinal Chemistry Letters, 13 (19). pp. 3227-3230. ISSN 0960-894X

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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.

Item Type: Article
Uncontrolled Keywords: binding sites,drug delivery systems,hexosyltransferases,mycobacterium tuberculosis,rhamnose,thiazolidinediones
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Computing Sciences
Depositing User: Pure Connector
Date Deposited: 17 Nov 2014 12:56
Last Modified: 21 Mar 2019 11:13
URI: https://ueaeprints.uea.ac.uk/id/eprint/50994
DOI: 10.1016/S0960-894X(03)00673-5

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