Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

Infectious diseases caused by bacterial pathogens area leadingcause of mortality worldwide. In particular, recalcitrant bacterialcommunities known as biofilms are implicated in persistent and difficultto treat infections. With a diminishing antibiotic pipeline, new treatmentsare urgently required to combat biofilm infections. An emerging strategyto develop new treatments is the hybridization of antibiotics. Thebenefit of this approach is the extension of the useful lifetime ofexisting antibiotics. The oxazolidinones, which include the last resortantibiotic linezolid, are an attractive target for improving antibiofilmefficacy as they present one of the most recently discovered classesof antibiotics. A key step in the synthesis of new 3-aryl-2-oxazolidinonederivatives is the challenging formation of the oxazolidinone ring.Herein we report a direct synthetic route to the piperazinyl functionalized3-aryl-2-oxazolidinone 17. We also demonstrate an applicationof these piperazine molecules by functionalizing them with a nitroxidemoiety as a strategy to extend the useful lifetime of oxazolidinonesand improve their potency against Methicillin-resistant Staphylococcusaureus (MRSA) biofilms. The antimicrobial susceptibilityof the linezolid-nitroxide conjugate 11 and its correspondingmethoxyamine derivative 12 (a control for biofilm dispersal)was assessed against planktonic cells and biofilms of MRSA. In comparisonto linezolid and our lead compound 10 (a piperazinyloxazolidinone derivative), the linezolid-nitroxide conjugate 11 displayed a minimum inhibitory concentration that was 4-16-foldhigher. The opposite effect was seen in biofilms where the linezolid-nitroxidehybrid 11 was >2-fold more effective (160 mu g/mLversus >320 mu g/mL) in eradicating MRSA biofilms. The methoxyaminederivative 12 performed on par with linezolid. The drug-likenessof the compounds was also assessed, and all compounds were predictedto have good oral bioavailability. Our piperazinyl oxazolidinone derivative 10 was confirmed to be lead-like and would be a good leadcandidate for future functionalized oxazolidinones. The modificationof antibiotics with a dispersal agent appears to be a promising approachfor eradicating MRSA biofilms and overcoming the antibiotic resistanceassociated with the biofilm mode of growth.

Automated summary

Infectious diseases caused by bacterial pathogens are a major cause of death worldwide. Biofilms, which are difficult to treat bacterial communities, are implicated in persistent infections. Hybridization of antibiotics is considered a promising strategy to combat biofilm infections. This study focused on the synthesis and modification of oxazolidinones, with the aim of extending their useful lifetime and improving their efficacy against MRSA biofilms. The results showed that the modification of antibiotics with a dispersal agent was effective in eradicating MRSA biofilms and overcoming antibiotic resistance.