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J Comb Chem. 2009 Jul-Aug;11(4):617-25. doi: 10.1021/cc9000357.

SAR studies for a new class of antibacterial NAD biosynthesis inhibitors.

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1
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.

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.

PMID:
19408950
PMCID:
PMC2888690
DOI:
10.1021/cc9000357
[Indexed for MEDLINE]
Free PMC Article
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