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PDBsum entry 4lae
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4lae
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of new dihydrofolate reductase antibacterial agents: 7-(Benzimidazol-1-Yl)-2,4-Diaminoquinazolines.
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Authors
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T.Lam,
M.T.Hilgers,
M.L.Cunningham,
B.P.Kwan,
K.J.Nelson,
V.Brown-Driver,
V.Ong,
M.Trzoss,
G.Hough,
K.J.Shaw,
J.Finn.
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Ref.
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J Med Chem, 2014,
57,
651-668.
[DOI no: ]
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PubMed id
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Abstract
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A new series of dihydrofolate reductase (DHFR) inhibitors, the
7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for
antibacterial potency and enzyme selectivity. The most potent inhibitors in this
series contained a five-membered heterocycle at the 2-position of the
benzimidazole, leading to highly potent and selective compounds that exploit the
differences in the size of a binding pocket adjacent to the NADPH cofactor
between the bacterial and human DHFR enzymes. Typical of these compounds is
7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent
inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over
human DHFR. This compound also has high antibacterial potency on Gram-positive
bacteria with an MIC versus wild type S. aureus of 0.0125 μg/mL and a MIC
versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus
a S. aureus septicemia was demonstrated, highlighting the potential of this new
series.
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