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.
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.
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. oluyinka.green@astrazeneca.com
Oluyinka M
OM
Green
Andrew R
AR
McKenzie
Adam B
AB
Shapiro
Ludovic
L
Otterbein
Haihong
H
Ni
Arthur
A
Patten
Suzanne
S
Stokes
Robert
R
Albert
Sameer
S
Kawatkar
Jason
J
Breed
D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D001667:Binding, Competitive; D020134:Catalytic Domain / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016415:Sequence Alignment; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C026146:N-acetylglucosamine-1-phosphate; D009713:Nucleotidyltransferases; C023226:UDPacetylglucosamine pyrophosphorylase; D000117:Acetylglucosamine