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PDBsum entry 4zvi
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References listed in PDB file
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Key reference
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Title
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N-Phenyl-4,5-Dibromopyrrolamides and n-Phenylindolamides as ATP competitive DNA gyrase b inhibitors: design, Synthesis, And evaluation.
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Authors
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N.Zidar,
H.Macut,
T.TomašIč,
M.Brvar,
S.Montalvão,
P.Tammela,
T.Solmajer,
L.Peterlin mašič,
J.Ilaš,
D.Kikelj.
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Ref.
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J Med Chem, 2015,
58,
6179-6194.
[DOI no: ]
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PubMed id
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Abstract
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Bacterial DNA gyrase is a well-known and validated target in the design of
antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase
B (GyrB), have so far not reached clinical use. In the present study, three
different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides
were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values
of compounds on DNA gyrase from Escherichia coli were in the low micromolar
range, with the best compound,
(4-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzoyl)glycine (18a), displaying an
IC50 of 450 nM. For this compound, a high-resolution crystal structure in
complex with E. coli DNA gyrase B was obtained, revealing details of its binding
mode within the active site. The binding affinities of three compounds with GyrB
were additionally evaluated by surface plasmon resonance, and the results were
in good agreement with the determined enzymatic activities. For the most
promising compounds, the inhibitory activities against DNA gyrase from
Staphylococcus aureus and topoisomerases IV from E. coli and S. aureus were
determined. Antibacterial activities of the most potent compounds of each series
were evaluated against two Gram-positive and two Gram-negative bacterial
strains. The results obtained in this study provide valuable information on the
binding mode and structure-activity relationship of
N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as promising classes of
ATP competitive GyrB inhibitors.
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