Abstract
A new lead class of antibacterial drug-like NAD synthetase (NADs) inhibitors was previously identified from a virtual screening study. Here a solution-phase synthetic library of 76 compounds, analogs of the urea-sulfonamide 5838, was synthesized in parallel to explore SAR on the sulfonamide aryl group. All library members were tested for enzyme inhibition against NADs and nicotinic acid mononucleotide adenylyltransferase (NaMNAT), the last two enzymes in the biosynthesis of NAD, and for growth inhibition in a Bacillus anthracis antibacterial assay. Most compounds that inhibited bacterial growth also showed inhibition against one of the enzymes tested. While only modest enhancements in the enzyme inhibition potency against NADs were observed, of significance was the observation that the antibacterial urea-sulfonamides more consistently inhibited NaMNAT.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amide Synthases / antagonists & inhibitors*
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Amide Synthases / metabolism
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Anthrax / drug therapy
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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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Bacillus anthracis / drug effects*
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Bacillus anthracis / enzymology*
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Humans
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Nicotinamide-Nucleotide Adenylyltransferase / antagonists & inhibitors
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Nicotinamide-Nucleotide Adenylyltransferase / metabolism
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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
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Urea / chemical synthesis
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Urea / chemistry*
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Urea / pharmacology
Substances
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Anti-Bacterial Agents
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Sulfonamides
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Urea
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Nicotinamide-Nucleotide Adenylyltransferase
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nicotinic acid mononucleotide adenylyltransferase
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Amide Synthases
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NAD+ synthase