Abstract
Glycosyltransferase MurG catalyses the transfer of N-acetyl-D-glucosamine to lipid intermediate I on the bacterial peptidoglycan biosynthesis pathway, and is a target for development of new antibacterial agents. A transition state mimic was designed for MurG, containing a functionalised proline, linked through the alpha-carboxylic acid, via a spacer, to a uridine nucleoside. A set of 15 functionalised prolines were synthesised, using a convergent dipolar cycloaddition reaction, which were coupled via either a glycine, proline, sarcosine, or diester linkage to the 5'-position of uridine. The library of 18 final compounds were tested as inhibitors of Escherichia coli glycosyltransferase MurG. Ten compounds showed inhibition of MurG at 1 mM concentration, the most active with IC50 400 mu M. The library was also tested against Mycobacterium tuberculosis galactosyltransferase GlfT2, and one compound showed effective inhibition at 1 mM concentration. (C) 2010 Elsevier Ltd. All rights reserved.
| Original language | English |
|---|---|
| Pages (from-to) | 2651-2663 |
| Number of pages | 13 |
| Journal | Bioorganic & Medicinal Chemistry |
| Volume | 18 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 1 Apr 2010 |
Keywords
- Peptidoglycan biosynthesis
- MurG
- Inhibition
- Mycobacterium tuberculosis
- Glycosyltransferase
