ABSTRACT
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/chemistry , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Phenyl Ethers/chemical synthesis , Pseudomonas Infections/drug therapy , Sulfides/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Catalytic Domain , Crystallography, X-Ray , Drug Resistance, Bacterial , Hydrogen Bonding , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mice , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Pseudomonas aeruginosa , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.