Design and synthesis of potent Gram-negative specific LpxC inhibitors

Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative b...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-02, Vol.21 (4), p.1155-1161
Main Authors: Faruk Mansoor, U., Vitharana, Dilrukshi, Reddy, Panduranga Adulla, Daubaras, Dayna L., McNicholas, Paul, Orth, Peter, Black, Todd, Arshad Siddiqui, M.
Format: Article
Language:English
Subjects:
Amidohydrolases - antagonists & inhibitors
Amidohydrolases - metabolism
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
antibacterial properties
antibiotics
Antibiotics. Antiinfectious agents. Antiparasitic agents
Benzodiazepinones - chemistry
Binding Sites
Biological and medical sciences
biosynthesis
Catalysis
Catalytic Domain
Crystallography, X-Ray
Drug Design
drugs
enzymes
Gram-negative
Gram-negative bacteria
Gram-Negative Bacteria - drug effects
hydrophobicity
Hydroxamic Acids - chemistry
lipid A
LpxC
Medical sciences
Microbial Sensitivity Tests
Pharmacology. Drug treatments
Structure-Activity Relationship
zinc
Zinc - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3- O-( R-3-hydroxymyristoyl)- N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme’s catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding ‘warheads’ lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.12.111