期刊论文详细信息
Molecules
Design and Synthesis of Various 5′-Deoxy-5′-(4-Substituted-1,2,3-Triazol-1-yl)-Uridine Analogues as Inhibitors of Mycobacterium tuberculosis Mur Ligases
Urmi Bajpai1  Ritu Arora1  Jyoti Rani1  Srinivasan Ramchandran2  Vincent Roy3  Vincent Hervin3  LuigiA. Agrofoglio3 
[1] Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, New Delhi 110019, India;G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi 110025, India;Institute of Organic and Analytical Chemistry, CNRS UMR 7311, Universite d’Orléans, Rue de Chartres, CEDEX 2, 45067 Orleans, France;
关键词: Mur ligase;    nucleoside analogues;    copper-catalyzed azide-alkyne cycloaddition;    antibacterial agents;    molecular modelling;   
DOI  :  10.3390/molecules25214953
来源: DOAJ
【 摘 要 】

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 μM. 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.

【 授权许可】

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