Design and synthesis of new hydroxyethylamines as inhibitors of d-alanyl-d-lactate ligase (VanA) and d-alanyl-d-alanine ligase (DdlB)

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 5, 2009, Pages 1376-1379

  Sova, Matej ^a   Čadež, Gašper ^a   Turk, Samo ^a   Majce, Vita ^a   Polanc, Slovenko ^a   Batson, Sarah ^b   Lloyd, Adrian J ^b   Roper, David I ^b   Fishwick, Colin W G ^c   Gobec, Stanislav ^a  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

^b UNIVERSITY OF WARWICK   (United Kingdom)

^c UNIVERSITY OF LEEDS   (United Kingdom)

Author keywords

Antibacterial agents; ATP dependant ligases; De novo molecular design; Enzyme inhibitors

Indexed keywords

BACTERIAL ENZYME; DEXTRO ALANINE DEXTRO ALANINE LIGASE; DEXTRO ALANINE DEXTRO LACTATE LIGASE; ETHYLAMINE; HYDROXYETHYLAMINE DERIVATIVE; HYDROXYL GROUP; HYDROXYLAMINE; LIGASE; LIGASE INHIBITOR; PHOSPHATE; UNCLASSIFIED DRUG; VANCOMYCIN;

ANTIBIOTIC RESISTANCE; ARTICLE; COMPETITIVE INHIBITION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; ENTEROCOCCUS FAECIUM; ENZYME ACTIVITY; ENZYME MECHANISM; ESCHERICHIA COLI; MOLECULE; REACTION ANALYSIS; STAPHYLOCOCCUS AUREUS;

BACTERIAL PROTEINS; CARBON-OXYGEN LIGASES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; ETHYLAMINES; PEPTIDE SYNTHASES;

ENTEROCOCCUS FAECIUM; ESCHERICHIA COLI; STAPHYLOCOCCUS AUREUS;

EID: 60449100155     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.01.034     Document Type: Article

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32. 2, 10 mM KCl, pH 7.5, 10% (v/v) DMSO with or without the compound, 2 mM PEP, 0.2 mM ATP, 1.972 units/mL PK, 2.46 units/mL LDH, 150 μM NADH and 4.3 mM d-Ala. Assays were followed spectrophotometrically at 37 °C, at 340 nm, and the reaction was initiated by the addition of DdlB (1.2 μg/mL), which gave an initial slope of -0.210 ± 0.032 (n = 6, uninhibited reaction). For VanA, the assays were carried out in the same manner as for DdlB above, except that the concentrations of the substrates in this case were 8 mM d-Ala, 1.78 mM d-Lac, and the reaction was initiated by the addition of VanA (37.5 μg/mL), which gave an initial slope of -0.215 ± 0.019 (n = 6, uninhibited reaction).
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34. HPLC analyses were performed on an Agilent Technologies HP 1100 instrument with G1365B UV-vis detector (254 nm), using a Luna C18 column (4.6 × 250 mm) at a flow rate of 1 mL/min. The eluant was a mixture of 0.1% TFA in water (A) and acetonitrile (B). The gradient was from 10% B to 80% B in 30 min (for compounds 6a and 6b) or 5% B to 95% B in 15 min (for compounds 7a and 7b).