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

• Published in: Bioorganic & medicinal chemistry letters 2003-10, Vol.13 (19), p.3227-3230
• Main Authors: Babaoglu, Kerim, Page, Mark A., Jones, Victoria C., McNeil, Michael R., Dong, Changjiang, Naismith, James H., Lee, Richard E.
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteriology; Binding Sites - drug effects; Binding Sites - physiology; Biological and medical sciences; Drug Delivery Systems - methods; Fundamental and applied biological sciences. Psychology; Hexosyltransferases - antagonists & inhibitors; Hexosyltransferases - biosynthesis; Medical sciences; Metabolism. Enzymes; Microbiology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Pharmacology. Drug treatments; Rhamnose - antagonists & inhibitors; Rhamnose - biosynthesis; Thiazolidinediones - chemistry; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00673-5

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 ≥50% inhibitory activity (at 20 μM) in the coupled rhamnose synthetic assay with seven of the 30 also having modest activity against whole-cell M. tuberculosis. The structure guided design and synthesis of thiazolidinone inhibitors of Mycobacterium tuberculosis dTDP-Rhamnose biosynthesis is described.