Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition
| Autor: | Gary E. Zurenko, Lester A. Dolak, Atli Thorarensen, Martin R. Douglas, J. C. Lynn, Eric P. Seest, Paul K. Tomich, James W. Nielsen, Michael T. Sweeney, Vincent D. Marshall, Anne F. Vosters, Michael John Bohanon, Anthony W. Yem, Douglas C. Rohrer, Randy M. Jensen |
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| Rok vydání: | 2001 |
| Předmět: |
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Molecular Staphylococcus aureus Protein Conformation Stereochemistry medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Hydroxamic Acids Aminopeptidases Biochemistry Chemical synthesis Amidohydrolases Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Molecular Biology Antibacterial agent chemistry.chemical_classification Hydroxamic acid Protease biology Chemistry fungi Organic Chemistry Metalloendopeptidases Active site Anti-Bacterial Agents body regions Enzyme nervous system Enzyme inhibitor biology.protein Molecular Medicine Antibacterial activity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 11:1355-1358 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/s0960-894x(01)00242-6 |
| Popis: | Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC 50 in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N- hydroxy urea 18 , which has both PDF and antibacterial activity. |
| Databáze: | OpenAIRE |
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