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.

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 16 Pg. 6389-409 (Aug 27 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26212502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Anti-Infective Agents
• Ether-A-Go-Go Potassium Channels
• Kcnh1 protein, mouse
• N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide
• Oxazoles
• Oxazolidinones
• Potassium Channel Blockers
• Tetrazolium Salts
• Thiazoles
• thiazolyl blue
• Linezolid

Topics

• Acetamides (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)
• Animals
• Anti-Infective Agents (chemical synthesis, pharmacology, toxicity)
• Bacteria (drug effects)
• Biological Availability
• Drug Design
• Ether-A-Go-Go Potassium Channels (drug effects)
• Linezolid
• Methicillin-Resistant Staphylococcus aureus
• Mice
• Microbial Sensitivity Tests
• Models, Molecular
• Oxazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Oxazolidinones (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)
• Potassium Channel Blockers (chemical synthesis, pharmacology)
• Staphylococcal Infections (drug therapy, microbiology)
• Structure-Activity Relationship
• Tetrazolium Salts
• Thiazoles