Discovery of a Teraryl Oxazolidinone Compound (<i>S</i>)‑<i>N</i>‑((3-(3-Fluoro-4-(4-(pyridin-2-yl)‑1<i>H</i>‑pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide Phosphate as a Novel Antimicrobial Agent with Enhanced Safety Profile and Efficacies

A series of novel teraryl oxazolidinone compounds was designed, synthesized, and evaluated for their antimicrobial activity and toxicities. The compounds with aromatic N-heterocyclic substituents at the 4-position of pyrazolyl ring showed better antibacterial activity against the tested bacteria than other compounds with different patterns of substitution. Among all potent compounds, <b>10f</b> exhibited promising safety profile in MTT assays and in hERG K⁺ channel inhibition test. Furthermore, its phosphate was found to be highly soluble in water (47.1 mg/mL), which is beneficial for the subsequent in vivo test. In MRSA systemic infection mice models, <b>10f</b> phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (<i>F</i> = 99.1%). Moreover, from the results of in vivo toxicology experiments, <b>10f</b> phosphate would be predicted to have less bone marrow suppression.