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

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journal contribution
posted on 2015-08-27, 00:00 authored by Tao Yang, Gong Chen, Zitai Sang, Yuanyuan Liu, Xiaoyan Yang, Ying Chang, Haiyue Long, Wei Ang, Jianying Tang, Zhenling Wang, Guobo Li, Shengyong Yang, Jingren Zhang, Yuquan Wei, Youfu Luo
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, 10f 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, 10f phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (F = 99.1%). Moreover, from the results of in vivo toxicology experiments, 10f phosphate would be predicted to have less bone marrow suppression.