Abstract
N-aryl-oxazolidinones is a prominent family of antimicrobials used for treating infections caused by clinically prevalent Gram-positive bacteria. Recently, boron-containing compounds have displayed intriguing potential in the antibiotic discovery setting. Herein, we report the unprecedented introduction of a boron-containing moiety such as an aryl boronic acid in the external region of the oxazolidinone structure via a chemoselective acyl coupling reaction. As a result, we accessed a series of analogues with a distal aryl boronic pharmacophore on the oxazolidinone scaffold. We identified that a peripheric linear conformation coupled with freedom of rotation and no further substitution on the external aryl boronic ring, an amido linkage with hydrogen bonding character, in addition to a para-relative disposition between boronic group and linker, are the optimal combination of structural features in this series for antimicrobial activity. In comparison to linezolid, the analogue comprising all those features, compound 20b, displayed levels of antimicrobial activity augmented by an eight-fold to a thirty-two-fold against a panel of Gram-positive strains, and a near one hundred-fold against Escherichia coli JW5503, a Gram-negative mutant strain with a defective efflux capability.
Highlights
The evaluation of novel pharmacophores in known and/-or unprecedented drug-like scaffolds is key to explore broad areas of the chemical space and unveil drug candidates with uncharted therapeutic profiles [1]
We selected the synthetic route reported by Frost and coworkers to prepare advanced intermediate 6 (Scheme 2) which they used as racemic synthon for the total syntheses of LZD, tedizolid and rivaroxaban.[21a] this route does not allow to control the configuration at the C-5 stereocentre of the central oxazolidinone ring, we considered that its relative efficiency, scalability, and modular character was quite convenient to swiftly access a series of aryl boronic analogues 10a-f with different substituents on the terminal aryl boronic ring
With all the data at hand we can conclude that 20b is the aryl boronic-containing oxazolidinone analogue with a combination of structural features ensuring better antimicrobial activities against the panel of clinically relevant GPB strains evaluated in this study
Summary
The evaluation of novel pharmacophores in known and/-or unprecedented drug-like scaffolds is key to explore broad areas of the chemical space and unveil drug candidates with uncharted therapeutic profiles [1] This approach is of utmost relevance in the antibiotic discovery setting [2], amidst the pre-pandemic global emergence of antimicrobial resistance (AMR) [3], that combined with a complex confluence of economic [4], regulatory [5], and societal factors drastically restricts the development of novel firstin-class antimicrobial drugs [6]. Unprecedented oxazolidinones featuring an aryl boronic acid ring in their peripheral west section
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