New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment

[Display omitted] The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor’s extra hydrophobic binding, providing us a useful tool for searching more efficient PDF in...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-08, Vol.26 (15), p.3714-3718
Main Authors: Lv, Fengping, Chen, Chen, Tang, Yang, Wei, Jianhai, Zhu, Tong, Hu, Wenhao
Format: Article
Language:English
Subjects:
Amide bioisosteres
Amidohydrolases - antagonists & inhibitors
Amidohydrolases - metabolism
Animals
Antibacterial drug
Antibiotics resistance
Docking study
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Humans
Male
Molecular Docking Simulation
Molecular Structure
MRSA
PDF inhibitor
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
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Summary:[Display omitted] The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor’s extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.05.077