Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase

• Published in: Bioorganic & medicinal chemistry letters 2005-05, Vol.15 (9), p.2305-2309
• Main Authors: Jarvest, Richard L., Erskine, Symon G., Forrest, Andrew K., Fosberry, Andrew P., Hibbs, Martin J., Jones, Joanna J., O’Hanlon, Peter J., Sheppard, Robert J., Worby, Angela
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Ethanolamines - chemical synthesis; Ethanolamines - pharmacology; Kinetics; Mammals; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Pharmacology. Drug treatments; Phenylalanine-tRNA Ligase - antagonists & inhibitors; Sensitivity and Specificity; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.03.003

High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified an ethanolamine as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition. High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.