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

Kerim Babaoglu, Mark A Page, Victoria C Jones, Michael R McNeil, Changjiang Dong, James H Naismith, Richard E Lee

Research output: Contribution to journalArticle

189 Citations (Scopus)

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 languageEnglish
Pages (from-to)3227-3230
Number of pages4
JournalBioorganic & Medicinal Chemistry Letters
Volume13
Issue number19
Early online date9 Aug 2003
DOIs
Publication statusPublished - 16 Oct 2003

Keywords

  • Binding Sites
  • Drug Delivery Systems
  • Hexosyltransferases
  • Mycobacterium tuberculosis
  • Rhamnose
  • Thiazolidinediones

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