title: Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Page
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Jones
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: Changjiang
authors.initials: C
authors.lastname: Dong
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D012210:Rhamnose / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D045162:Thiazolidinediones; D006602:Hexosyltransferases; C025816:LPS rhamnosyltransferases; D012210:Rhamnose