Design, Synthesis, and Antibacterial Evaluation of Novel Non‐Oxazolidinone Analogues of Linezolid to Investigate the Role of the Oxazolidinone Ring

ABSTRACT

A new series of non‐oxazolidinone derivatives 5a–d and 6 was designed and synthesized as potential analogues of Linezolid. The aim of this work was to develop compounds with improved antibacterial activity, the ability to overcome bacterial resistance, and reduced toxicity. The synthesized compounds were evaluated for their in vitro antimicrobial activity against several pathogenic Gram‐positive and Gram‐negative bacterial strains, including multidrug‐resistant isolates (MRSA). In addition, a probability of resistance development assay was performed to assess their potential to induce bacterial resistance. The biological evaluation revealed that all synthesized derivatives exhibited lower antibacterial activity compared to Linezolid and gentamycin, highlighting the crucial role of the oxazolidinone ring in its antibacterial activity. Molecular docking studies were conducted to investigate the binding mode of the new compounds within the active site of the 50S ribosomal subunit. The docking results showed lacking structural superimposition with Linezolid within the binding pocket, and lacking several key interactions required for strong binding, which may explain their reduced antibacterial potency relative to the reference drug.