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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-10, Vol.25 (21), p.4953
• Main Authors: Hervin, Vincent, Arora, Ritu, Rani, Jyoti, Ramchandran, Srinivasan, Bajpai, Urmi, Agrofoglio, Luigi A, Roy, Vincent
• Format: Article
• Language: English
• Subjects: Alcohol; Alkynes; Amino acids; antibacterial agents; Antibiotics; Binding sites; Biological activity; Biosynthesis; Catalytic Domain; Chemistry Techniques, Synthetic; copper-catalyzed azide-alkyne cycloaddition; Cycloaddition; Drug Design; Drug resistance; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Hydrogen bonds; Inhibitors; Ligands; Molecular docking; Molecular Docking Simulation; Molecular dynamics; molecular modelling; Mur ligase; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; N-Acetylglucosamine; nucleoside analogues; Peptide Synthases - antagonists & inhibitors; Peptide Synthases - chemistry; Peptide Synthases - metabolism; Peptidoglycans; Proteins; Simulation; Substitutes; Triazoles - chemistry; Tuberculosis; Uridine; Uridine - chemical synthesis; Uridine - chemistry; Uridine - pharmacology
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25214953

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 (Mtb), are described. Starting from UDP- -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, -acetylglucosamine analogues and 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 and are occupying the active site of Mtb MurE ligase.