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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

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 substr...

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Autores principales: Hervin, Vincent, Arora, Ritu, Rani, Jyoti, Ramchandran, Srinivasan, Bajpai, Urmi, Agrofoglio, Luigi A., Roy, Vincent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663697/
https://www.ncbi.nlm.nih.gov/pubmed/33114668
http://dx.doi.org/10.3390/molecules25214953
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author Hervin, Vincent
Arora, Ritu
Rani, Jyoti
Ramchandran, Srinivasan
Bajpai, Urmi
Agrofoglio, Luigi A.
Roy, Vincent
author_facet Hervin, Vincent
Arora, Ritu
Rani, Jyoti
Ramchandran, Srinivasan
Bajpai, Urmi
Agrofoglio, Luigi A.
Roy, Vincent
author_sort Hervin, Vincent
collection PubMed
description 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.
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spelling pubmed-76636972020-11-14 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 Hervin, Vincent Arora, Ritu Rani, Jyoti Ramchandran, Srinivasan Bajpai, Urmi Agrofoglio, Luigi A. Roy, Vincent Molecules Article 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. MDPI 2020-10-26 /pmc/articles/PMC7663697/ /pubmed/33114668 http://dx.doi.org/10.3390/molecules25214953 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hervin, Vincent
Arora, Ritu
Rani, Jyoti
Ramchandran, Srinivasan
Bajpai, Urmi
Agrofoglio, Luigi A.
Roy, Vincent
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663697/
https://www.ncbi.nlm.nih.gov/pubmed/33114668
http://dx.doi.org/10.3390/molecules25214953
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