Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

Abstract

Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Light‐Driven Kinetic Resolution of α‐Functionalized Carboxylic Acids Enabled by an Engineered Fatty Acid Photodecarboxylase

“…The enantioenriched products can be transformed into a variety of complex biologically active molecules. For example, ( R )‐ 1 b is the chiral precursor of the antimicrobial natural product Lipoxazolidinone A or the essential building block of a series of novel neutral thrombin inhibitors (Scheme ).…”

5‐Benzylidene‐4‐Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms

“…Representative examples include the 2‐aminoimidazoles (2AI), meridianin D analogues, halogenated quinolines, hydroxybenzylidene‐indolinones, bromophenol‐thiohydantoins, and 2‐dichloroalkyl‐5‐benzylidene‐4‐oxazolidinones . During our initial investigation into the 2‐dichloroalkyl‐4‐oxazolidinones, and as part of our broader program to develop novel 4‐oxazolidinone antimicrobial agents, we identified potent biofilm‐inhibiting and ‐dispersing agents, and established an initial structure–activity relationship (SAR) for these synoxazolidinone natural‐product analogues (Figure A). Herein, we expand on the SAR of these synoxazolidinone analogues and explore their ability to act in concert with common antibiotics against S. aureus biofilms (Figure B).…”

Synform Issue 2018/9

“…The second is my own group's efforts to develop the lipox azolidinone family of natural products (Scheme 1). 6 We have developed a rapid approach for their synthesis, optimized novel analogues with improved activity and have de monstrated that these 4-oxazolidinone heterocycles inhibit both protein synthesis and cellwall biosynthesis in Gram positive bacteria. These efforts, in addition to an array of additional studies, provide the groundwork for a comprehensive effort to advance the 4oxazolid inones as potential antibiotics.…”