SAR studies for a new class of antibacterial NAD biosynthesis inhibitors.
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.
Moro
Whitney Beysselance
WB
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.
Yang
Zhengrong
Z
Kane
Tasha A
TA
Zhou
Qingxian
Q
Harville
Steve
S
Brouillette
Christie G
CG
Brouillette
Wayne J
WJ
D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000881:Anthrax / Q000188:drug therapy; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D013449:Sulfonamides; D014508:Urea; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase; D019732:Amide Synthases; C038479:NAD+ synthase