jm5b00152_si_001.pdf (362.08 kB)
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
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 LuoA 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.
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pyrazolyl ringvivo testsurvival protectionbone marrow suppressioninfection mice modelsEfficaciesA seriesnovel teraryl oxazolidinone compoundsMTT assayshERG KNovel Antimicrobial Agentsafety profilechannel inhibition testantimicrobial activity10 f phosphateTeraryl Oxazolidinonevivo toxicology experiments10 fEnhanced Safety ProfileMRSA
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