2-Aminotetralones: Novel inhibitors of MurA and MurZ

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 5; pp. 1730 - 1734
• Main Authors: Dunsmore, Colin J., Miller, Keith, Blake, Katy L., Patching, Simon G., Henderson, Peter J.F., Garnett, James A., Stubbings, William J., Phillips, Simon E.V., Palestrant, Deborah J., Angeles, Joseph De Los, Leeds, Jennifer A., Chopra, Ian, Fishwick, Colin W.G.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2008; Elsevier
• Subjects: 2-Aminotetralone; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins - antagonists & inhibitors; Binding Sites; Biochemistry, Molecular Biology; Biological and medical sciences; Chemical Sciences; Escherichia coli; Escherichia coli - drug effects; Life Sciences; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; MurA inhibitor; MurZ inhibitor; Organic chemistry; Pharmacology. Drug treatments; Radiochemistry; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Tetralones - chemistry; Tetralones - pharmacology; MurA inhibitor; 2-Aminotetralone; Antibacterial activity; MurZ inhibitor; Enzyme; Transferases; Escherichia coli; Active site; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Modeling; Structure activity relation; UDP-N-acetylglucosamine 1-carboxyvinyltransferase; Molecular model; Bacteria; Micrococcales; Micrococcaceae; Piperazine derivatives; Antibacterial agent; Chemical synthesis; Staphylococcus aureus; Enterobacteriaceae
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.01.089

A new series of inhibitors of Escherichia coli MurA and Staphylococcus aureus MurA and MurZ having useful antibacterial properties are reported. Several 2-aminotetralones were identified as novel inhibitors of the bacterial enzymes MurA and MurZ. A number of these inhibitors demonstrated antibacterial activity against Staphylococcus aureus and Escherichia coli with MICs in the range 8–128 μg/ml. Based on structure–activity relationships we propose that the α-aminoketone functionality is responsible for the inhibitory activity and evidence is provided to support a covalent mode of action involving the C115 thiol group of MurA/MurZ.