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Issue 26, 2015
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5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

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Abstract

The straightforward synthesis of 5′-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5′ methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC50 ranging from 15 to 150 μM. A molecular modeling study was performed to rationalize the observed structure–activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraYAA. The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 μg mL−1, including the methicillin resistant Staphylococcus aureus (MRSA).

Graphical abstract: 5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

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Publication details

The article was received on 08 Apr 2015, accepted on 06 May 2015 and first published on 06 May 2015


Article type: Paper
DOI: 10.1039/C5OB00707K
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2015,13, 7193-7222
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    5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

    M. J. Fer, A. Bouhss, M. Patrão, L. Le Corre, N. Pietrancosta, A. Amoroso, B. Joris, D. Mengin-Lecreulx, S. Calvet-Vitale and C. Gravier-Pelletier, Org. Biomol. Chem., 2015, 13, 7193
    DOI: 10.1039/C5OB00707K

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