Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1510-9. doi: 10.1016/j.bmcl.2012.01.016. Epub 2012 Jan 14.

Abstract

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40.

MeSH terms

  • Acetylglucosamine / analogs & derivatives
  • Acetylglucosamine / chemistry
  • Acetylglucosamine / pharmacology
  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacteria / drug effects
  • Bacteria / genetics
  • Binding, Competitive
  • Catalytic Domain / drug effects*
  • Crystallography, X-Ray
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Nucleotidyltransferases / antagonists & inhibitors*
  • Nucleotidyltransferases / chemistry
  • Sequence Alignment
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Sulfonamides
  • N-acetylglucosamine-1-phosphate
  • Nucleotidyltransferases
  • UDPacetylglucosamine pyrophosphorylase
  • Acetylglucosamine