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

Oluyinka M Green; Andrew R McKenzie; Adam B Shapiro; Ludovic Otterbein; Haihong Ni; Arthur Patten; Suzanne Stokes; Robert Albert; Sameer Kawatkar; Jason Breed

doi:10.1016/j.bmcl.2012.01.016

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.

Authors

Oluyinka M Green¹, Andrew R McKenzie, Adam B Shapiro, Ludovic Otterbein, Haihong Ni, Arthur Patten, Suzanne Stokes, Robert Albert, Sameer Kawatkar, Jason Breed

Affiliation

¹ Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. [email protected]

PMID: 22297115
DOI: 10.1016/j.bmcl.2012.01.016

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