ABSTRACT
The synoxazolidinone family of marine natural products bear an unusual 4-oxazolidinone heterocyclic core and promising antimicrobial activity against several strains of pathogenic bacteria. As part of our research program directed at the synthesis and chemical biology of this family of natural products we have developed a one-step method for the generation of variously substituted 4-oxazolidinone scaffolds from readily available materials. These studies revealed the importance of an electron deficient aromatic ring for antimicrobial activity and serve as the basis for future SAR studies around the 4-oxazolidinone core.
Subject(s)
Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of ß-lactam antibiotics by up to 64-fold.
Subject(s)
Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Small Molecule Libraries/pharmacology , beta-Lactam Resistance/drug effects , Animals , Cell Line , Cell Survival/drug effects , Gram-Negative Bacteria/classification , Hemolysis/drug effects , Humans , Keratinocytes/cytology , Keratinocytes/drug effects , Microbial Sensitivity Tests , Sheep , Small Molecule Libraries/chemistryABSTRACT
A five-step total synthesis of the marine natural product synoxazolidinoneâ A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4-oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.
