Multiparameter Optimization of Broad-Spectrum Antibacterial Activity, ADMET Properties, and MAO-A/B Inhibition of Novel Biaryloxazolidinone-Hydrazone Derivatives: Identification of a Lead with In Vivo Efficacy against Linezolid-Resistant <i>Staphyloc

In our previous study, oxazolidinone <b>EJMC</b>-<b>8b</b> demonstrated potent antibacterial activity and drug-likeness but was limited by MAO-A inhibition, high plasma protein binding, and inferior in vivo efficacy compared to linezolid. Herein, we report the discovery of a promising compound <b>D13</b>, which exhibited excellent antibacterial activity against <i>S. aureus</i>, MSSA, MRSA, LRSA, and LREFa with MIC values of <0.03, 0.125, 0.25, <0.03, and 1 μg/mL, respectively. Subsequently, <b>D13</b> displayed significantly reduced MAO-A and MAO-B inhibition (IC₅₀ = 51.3 and 47.0 μM, respectively) and superior PK profiles (<i>F</i> = 113.1%) in mice. Ultimately, compound <b>D13</b> demonstrated potent and dose-dependent efficacy in vivo in a mouse model of LRSA peritonitis infection. However, compound <b>D13</b> showed potential cytotoxicity and mitochondrial toxicity, although it does not have acute toxicity in mice. Through our comprehensive studies, compound <b>D13</b> has emerged as a promising back-up compound for the treatment of linezolid-resistant bacterial infections and deserves further research.