Design, synthesis and biological evaluation of urea derivatives from o-hydroxybenzylamines and phenylisocyanate as potential FabH inhibitors

Zi-Lin Li; Qing-Shan Li; Hong-Jia Zhang; Yang Hu; Di-Di Zhu; Hai-Liang Zhu

doi:10.1016/j.bmc.2011.06.049

Design, synthesis and biological evaluation of urea derivatives from o-hydroxybenzylamines and phenylisocyanate as potential FabH inhibitors

Bioorg Med Chem. 2011 Aug 1;19(15):4413-20. doi: 10.1016/j.bmc.2011.06.049. Epub 2011 Jun 25.

Authors

Zi-Lin Li¹, Qing-Shan Li, Hong-Jia Zhang, Yang Hu, Di-Di Zhu, Hai-Liang Zhu

Affiliation

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.

PMID: 21752655
DOI: 10.1016/j.bmc.2011.06.049

Abstract

FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of o-hydroxybenzylamines 1-16 and its corresponding new urea derivatives 17-32 were synthesized and fully characterized by spectroscopic methods and elemental analysis. This new urea derivatives class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-bromo-2-hydroxybenzyl)-1-(4-fluorophenyl)-3-phenylurea (18) and 1-(5-bromo-2-hydroxybenzyl)-1-(4-chlorophenyl)-3-phenylurea (20) were potent inhibitors of E. coli FabH.

Publication types

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

MeSH terms

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects*
Bacteria / enzymology*
Bacterial Infections / drug therapy
Bacterial Infections / enzymology
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Escherichia coli / enzymology
Escherichia coli Infections / drug therapy
Escherichia coli Infections / enzymology
Gram-Negative Bacteria
Humans
Microbial Sensitivity Tests
Models, Molecular
Protein Binding
Urea / analogs & derivatives*

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Urea
3-ketoacyl-acyl carrier protein synthase III
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase