期刊
MOLECULES
卷 25, 期 21, 页码 -出版社
MDPI
DOI: 10.3390/molecules25214953
关键词
Mur ligase; nucleoside analogues; copper-catalyzed azide-alkyne cycloaddition; antibacterial agents; molecular modelling
资金
- University of Orleans, CNRS
- LabEx SYNORG [ANR-11-LABX-0029]
- LabEx SYNORG
- Indian Council of Medical Research (ICMR)
- University Grant Commission (UGC)
- Science and Engineering Research Board (SERB), DST, GoI
The synthesis of hitherto unknown 5 '-deoxy-5 '-(4-substituted-1,2,3-triazol-1-yl)-uridine and its evaluation, through an one-pot screening assay, against MurA-F enzymes involved in Mycobacterium tuberculosis (Mtb), are described. Starting from UDP-N-acetylmuramic acid (UDP-MurNAc), the natural substrate involved in the peptidoglycan biosynthesis, our strategy was to substitute the diphosphate group of UDP-MurNAc by a 1,2,3-triazolo spacer under copper-catalyzed azide-alkyne cycloaddition conditions. The structure-activity relationship was discussed and among the 23 novel compounds developed, N-acetylglucosamine analogues 11c and 11e emerged as the best inhibitors against the Mtb MurA-F enzymes reconstruction pathway with an inhibitory effect of 56% and 50%, respectively, at 100 mu M. Both compounds are selective inhibitors of Mtb MurE, the molecular docking and molecular dynamic simulation suggesting that 11c and 11e are occupying the active site of Mtb MurE ligase.
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