Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

Abstract

Natural products have historically been am ajor 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,r epresents an ew scaffold for antimicrobial discovery;h owever,q uestions 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,a nd 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.

A Scientific Ethnomedical Study Using Microbes on Gaucher Disease: An In-Silico Analysis

“…In line with our findings, the bioactive compound Lipoxazolidinone C has unusual 4-oxazolidinone heterocycle at its core, representing a wide spectrum of antibacterial and anti-microbial activity similar to those of the commercial antibiotic linezolid (Zyvox) [16]. Another study suggests that 4-oxazolidinones are valuable scaffolds of antimicrobial development [17]. Cinnamic acid and its phenolic analogs are natural substances.…”

Expanded Structure–Activity Studies of Lipoxazolidinone Antibiotics

“…15 Previously, our group has synthesized analogs of the lipoxazolidinones that are potent against methicillin susceptible S. aureus (MSSA) and MRSA; however, these analogs have potential liabilities, including high lipophilicity. 16,17 Since little was known regarding the SAR of the right-hand domain of the lipoxazolidinones, we drew inspiration from one of the analogs that we previously synthesized (6, Figure 2), which had similar antimicrobial activity against MSSA and MRSA to that of the natural product, and a cLogP of 3.84, compared to a cLogP of 6.66 for 1 and 5.26 for simplified analog 5 (Figure 2). 16 Inspired to further explore this initial result, the goal of this study was 2-fold: first, we planned to synthesize a panel of aryl derivatives aiming to maintain high levels of antimicrobial activity while exploring the effect of aryl substitution patterns; second, we sought to vary chain lengths and install more polar functionality around the aromatic ring to further elucidate the structure−activity relationship for these aryl derivatives and the oxazolidinones more broadly.…”

“…16,17 Since little was known regarding the SAR of the right-hand domain of the lipoxazolidinones, we drew inspiration from one of the analogs that we previously synthesized (6, Figure 2), which had similar antimicrobial activity against MSSA and MRSA to that of the natural product, and a cLogP of 3.84, compared to a cLogP of 6.66 for 1 and 5.26 for simplified analog 5 (Figure 2). 16 Inspired to further explore this initial result, the goal of this study was 2-fold: first, we planned to synthesize a panel of aryl derivatives aiming to maintain high levels of antimicrobial activity while exploring the effect of aryl substitution patterns; second, we sought to vary chain lengths and install more polar functionality around the aromatic ring to further elucidate the structure−activity relationship for these aryl derivatives the oxazolidinones more broadly. Utilizing a synthetic approach that was previously developed and optimized to a one-pot procedure by our group, we were able to synthesize a panel of 26 oxazolidinone analogs (Figure 3).…”