Abstract
The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.
MeSH terms
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Drug Design
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology
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Microbial Sensitivity Tests
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Models, Molecular
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N-Glycosyl Hydrolases / antagonists & inhibitors*
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N-Glycosyl Hydrolases / chemistry
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Neisseria meningitidis / drug effects
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Streptococcus pneumoniae / drug effects
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Streptococcus pyogenes / drug effects
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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3',4'-dichlorobiphenyl-3-sulfonic acid (3-chloro-7-isobutylamino-1H-indazol-5-yl)amide
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Anti-Bacterial Agents
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Indazoles
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Sulfonamides
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N-Glycosyl Hydrolases
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adenosylhomocysteine nucleosidase