Abstract |
The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
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Authors | Jared T Spletstoser, Jason Dreabit, Andrew N Knox, Andrew Benowitz, Nino Campobasso, Paris Ward, Guanglei Cui, Thomas Lewandowski, Lynn McCloskey, Kelly M Aubart |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 29
Issue 16
Pg. 2410-2414
(08 15 2019)
ISSN: 1464-3405 [Electronic] England |
PMID | 31160176
(Publication Type: Journal Article)
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Copyright | Copyright © 2019 Elsevier Ltd. All rights reserved. |
Chemical References |
- Anti-Bacterial Agents
- Enzyme Inhibitors
- Pyridazines
- piperazic acid
- Amidohydrolases
- peptide deformylase
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Topics |
- Amidohydrolases
(antagonists & inhibitors, metabolism)
- Anti-Bacterial Agents
(chemical synthesis, chemistry, pharmacology)
- Crystallography, X-Ray
- Dose-Response Relationship, Drug
- Drug Discovery
- Enzyme Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Haemophilus influenzae
(drug effects, enzymology)
- Microbial Sensitivity Tests
- Models, Molecular
- Molecular Structure
- Pyridazines
(chemical synthesis, chemistry, pharmacology)
- Respiratory Tract Infections
(drug therapy, metabolism)
- Skin Diseases, Infectious
(drug therapy, metabolism)
- Staphylococcus aureus
(drug effects, enzymology)
- Streptococcus pneumoniae
(drug effects, enzymology)
- Structure-Activity Relationship
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