title: Discovery of novel bis-oxazolidinone compounds as potential potent and selective antitubercular agents.
abstract: A variety of new mono-oxazolidinone molecules by modifying the C-ring of Linezolid, a marketed antibiotic for MRSA, were synthesized and tested for their in vitro antibacterial activities against several Staphylococcus aureus, Mycobacterium smegmatis and two Gram-negative bacteria strains (Escherichia coli and Pseudomonas aeruginosa). Among them, compounds 4-7 displayed moderate antimicrobial activities. After development of a second oxazolidinone ring in the western part of the mono-oxazolidinone compounds 4-7 by a ring closure reaction with N,N'-carbonyldiimidazole (CDI), we found thus obtained bis-oxazolidinone compounds 22-25 possess excellently inhibitory activities against H37Rv but poor or no effects on other test bacteria. Among them, bis-oxazolidinone compound 22 and 24 are the most potent two compounds with a same MIC value of 0.125μg/mL against H37Rv virulent strain. Compound 22 also exhibited extremely low cytotoxicity on monkey kidney Vero cells with a selective index (IC50/MIC) over 40,000, which suggested bis-oxazolidinone compound 22 is a promising lead compound for subsequent investigation in search of new antitubercular agents.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ang
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Zitai
authors.initials: Z
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: luo_youfu@scu.edu.cn.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D023303:Oxazolidinones
keywords: Antitubercular; Bis-oxazolidinone; Selectivity; Tuberculosis; Vero cells