Expanded Structure-Activity Studies of Lipoxazolidinone Antibiotics.

The lipoxazolidinone family of marine natural products, which contains an unusual 4-oxazolidinone core, was found to possess potent antimicrobial activity against methicillin resistant (MRSA). Herein, we expanded our previous synthetic efforts by preparing selected aryl derivatives of the lipoxazolidinones and further evaluating the potential to expand the activity of this class of molecules to Gram-negative pathogens. With these analogs, we explored the effect of varying the substitution pattern around the aromatic ring, increasing the chain length between the oxazolidinone core and the aryl system, and how altering the position of more polar functional groups affected the antimicrobial activity.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A.

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.