We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB.
- Authors
Hrast, Martina; Jukič, Marko; Patin, Delphine; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Barreteau, Hélène; Gobec, Stanislav
- Abstract
In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP‐<italic>N</italic>‐acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+, a pharmacophore model was generated and used in a virtual screening campaign with combined structure‐based and ligand‐based approaches. To explore chemical space around hit compounds, further similarity search and organic synthesis were employed to obtain several compounds with micromolar IC50 values on MurB. The best inhibitors in the reported series of 5‐substituted tetrazol‐2‐yl acetamides were compounds <bold>13</bold>,<bold> 26</bold> and <bold>30</bold> with IC50 values of 34, 28 and 25 μ m, respectively. None of the reported compounds possessed in vitro antimicrobial activity against <italic>Staphylococcus aureus</italic> and <italic>Escherichia coli</italic>.
- Subjects
ANTIBACTERIAL agents; CRYSTAL structure; ORGANIC synthesis; ENZYME analysis; DRUG development
- Publication
Chemical Biology & Drug Design, 2018, Vol 91, Issue 6, p1101
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13172