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.
Keywords:
Antibacterial; Peptide deformylase; Piperazic acid; Reverse hydroxamate; Sch-382583.
Copyright © 2019 Elsevier Ltd. All rights reserved.
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Haemophilus influenzae / drug effects
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Haemophilus influenzae / enzymology
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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Pyridazines / chemical synthesis
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Pyridazines / chemistry
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Pyridazines / pharmacology*
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Respiratory Tract Infections / drug therapy*
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Respiratory Tract Infections / metabolism
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Skin Diseases, Infectious / drug therapy*
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Skin Diseases, Infectious / metabolism
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology
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Streptococcus pneumoniae / drug effects
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Streptococcus pneumoniae / enzymology
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Pyridazines
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piperazic acid
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Amidohydrolases
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peptide deformylase