Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria

Shouning Yang; Wei Shi; Dong Xing; Zheng Zhao; Fengping Lv; Liping Yang; Yushe Yang; Wenhao Hu

doi:10.1016/j.ejmech.2014.07.106

Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria

Eur J Med Chem. 2014 Oct 30:86:133-52. doi: 10.1016/j.ejmech.2014.07.106. Epub 2014 Aug 12.

Authors

Shouning Yang¹, Wei Shi¹, Dong Xing¹, Zheng Zhao², Fengping Lv¹, Liping Yang¹, Yushe Yang³, Wenhao Hu⁴

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China.
² Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China. Electronic address: [email protected].
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
⁴ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, East China Normal University, Shanghai 200062, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].

PMID: 25151577
DOI: 10.1016/j.ejmech.2014.07.106

Abstract

Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.

Keywords: Drug resistant bacteria; Peptide deformylase inhibitor; Proline derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects*
Dose-Response Relationship, Drug
Drug Resistance, Bacterial / drug effects*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Oligopeptides / chemical synthesis
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Oligopeptides
Amidohydrolases
peptide deformylase