title: 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.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Zitai
authors.initials: Z
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Long
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ang
authors.affiliation: Sichuan Good Doctor Pharmaceutical Co., Ltd. , Chengdu, Sichuan 610031, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Guobo
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Centre for Infectious Diseases Research, School of Medicine, Tsinghua University , Beijing, 100084, China.
authors.forename: Jingren
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D001682:Biological Availability; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D051638:Ether-A-Go-Go Potassium Channels; C496885:Kcnh1 protein, mouse; C000602645:N-((3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide; D010080:Oxazoles; D023303:Oxazolidinones; D026902:Potassium Channel Blockers; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D000069349:Linezolid