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Bioorganic and Medicinal Chemistry Letters
Volumn 24, Issue 1, 2014, Pages 353-359
Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ
Author keywords

3 Methoxybenzamide; Antibacterial; Cell division; FtsZ; MRSA
Indexed keywords

ALANINE; ANTIBIOTIC AGENT; BENZAMIDE DERIVATIVE; FTSZ PROTEIN; GLYCINE; LINEZOLID; OXAZOLE DERIVATIVE; VANCOMYCIN;
EID: 84891488904     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2013.11.002     Document Type: Article
Times cited : (79)
References (22)
  • 13
    • 84891484402 scopus 로고    scopus 로고
    • Clinical and Laboratory Standards Institute. CLSI Document M7-A7. Clinical and Laboratory Standards Institute, Wayne, PA.
    • Clinical and Laboratory Standards Institute. CLSI Document M7-A7. Clinical and Laboratory Standards Institute, Wayne, PA.
  • 16
    • 84891485963 scopus 로고    scopus 로고
    • Groups of healthy adult male Balb/c mice received compounds by intravenous (IV) or oral (PO) administration at a dose level of 3 mg/kg. In all cases the dose volume was 5 mL/kg. Compounds were formulated in 10% dimethyl sulfoxide (DMSO), 40% tetraethylene glycol (TEG), and 20% 2-hydroxypropyl- β-cyclodextrin (HPβCD) in water (final). At various time points, samples of blood were collected for analysis. Three animals were used for each time point. Total plasma concentrations of compounds were measured by LC-MS/MS and pharmacokinetic parameters were calculated using Win-Nonlin.
    • Groups of healthy adult male Balb/c mice received compounds by intravenous (IV) or oral (PO) administration at a dose level of 3 mg/kg. In all cases the dose volume was 5 mL/kg. Compounds were formulated in 10% dimethyl sulfoxide (DMSO), 40% tetraethylene glycol (TEG), and 20% 2-hydroxypropyl- β-cyclodextrin (HPβCD) in water (final). At various time points, samples of blood were collected for analysis. Three animals were used for each time point. Total plasma concentrations of compounds were measured by LC-MS/MS and pharmacokinetic parameters were calculated using Win-Nonlin.
  • 17
    • 84891488509 scopus 로고    scopus 로고
    • 2 at ambient temperature for 48 h.
    • 2 at ambient temperature for 48 h.
  • 19
    • 84891494627 scopus 로고    scopus 로고
    • In addition to the steps shown explicitly, phenyl oxazole 21 was prepared via Suzuki coupling of the appropriate oxazolyl bromide. Compounds 16, 17, 19 and 22 were prepared from the corresponding oxazolyl bromide by means of Stille coupling and, where required, subsequent Pd-catalysed hydrogenation. 5-Chloro-and 5-iodo-oxazoles 25 and 27 were synthesised in a manner analogous to 26 using N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS) in place of N-bromosuccinimide (NBS). Trifluoromethyl derivative 28 was prepared by treatment of the appropriate oxazolyl iodide intermediate with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and copper(I) iodide in HPMA and N,N-dimethylformamide (DMF).
    • In addition to the steps shown explicitly, phenyl oxazole 21 was prepared via Suzuki coupling of the appropriate oxazolyl bromide. Compounds 16, 17, 19 and 22 were prepared from the corresponding oxazolyl bromide by means of Stille coupling and, where required, subsequent Pd-catalysed hydrogenation. 5-Chloro-and 5-iodo-oxazoles 25 and 27 were synthesised in a manner analogous to 26 using N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS) in place of N-bromosuccinimide (NBS). Trifluoromethyl derivative 28 was prepared by treatment of the appropriate oxazolyl iodide intermediate with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and copper(I) iodide in HPMA and N,N-dimethylformamide (DMF).
  • 20
    • 84891490971 scopus 로고    scopus 로고
    • Enantiomers 48 and 3 were separated from a 1 g sample of the racemic mixture 36 using a CHIRALPAK® AD-H, (250 × 30) mm, 5 μm 5 122 column with a n-hexane/EtOH/MeOH (80:10:10 v/v/v) mobile phase.
    • Enantiomers 48 and 3 were separated from a 1 g sample of the racemic mixture 36 using a CHIRALPAK® AD-H, (250 × 30) mm, 5 μm 5 122 column with a n-hexane/EtOH/MeOH (80:10:10 v/v/v) mobile phase.
  • 21
    • 84891491081 scopus 로고    scopus 로고
    • The kinetic solubility of the compounds was measured using a turbidimetric method. A series of doubling dilutions of compounds were prepared in neat DMSO. Five microlitre samples were diluted twenty-fold into 95 μL volumes of phosphate buffered saline (PBS, pH 7.4) in microtiter assay plates and allowed to reach equilibrium at room temperature for 24 h. The absorbance within each well of the plate was read spectrophotometrically at a wavelength of 620 nm. A precipitate forms when the maximum aqueous solubility level is reached. The value quoted is the highest concentration where the compound was in solution, that is, where no measurable precipitate was present.
    • The kinetic solubility of the compounds was measured using a turbidimetric method. A series of doubling dilutions of compounds were prepared in neat DMSO. Five microlitre samples were diluted twenty-fold into 95 μL volumes of phosphate buffered saline (PBS, pH 7.4) in microtiter assay plates and allowed to reach equilibrium at room temperature for 24 h. The absorbance within each well of the plate was read spectrophotometrically at a wavelength of 620 nm. A precipitate forms when the maximum aqueous solubility level is reached. The value quoted is the highest concentration where the compound was in solution, that is, where no measurable precipitate was present.

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