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 Staphylococcus aureus.

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