title: 5'-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling.
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).
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, CICB-Paris (Centre Interdisciplinaire Chimie Biologie-Paris), 45 rue des Saints Pères, 75270 Paris 06, France. christine.gravier-pelletier@parisdescartes.fr sandrine.calvet-vitale@parisdescartes.fr.
authors.forename: Mickaël J
authors.initials: MJ
authors.lastname: Fer
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bouhss
authors.forename: Mariana
authors.initials: M
authors.lastname: Patrão
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Corre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Dominique
authors.initials: D
authors.lastname: Mengin-Lecreulx
authors.forename: Sandrine
authors.initials: S
authors.lastname: Calvet-Vitale
authors.forename: Christine
authors.initials: C
authors.lastname: Gravier-Pelletier
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017855:Transferases (Other Substituted Phosphate Groups); D014230:Triazoles / Q000737:chemistry*; D014529:Uridine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014230:Triazoles; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria; D014529:Uridine