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Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria

文献类型：期刊论文

作者Liu, Fangjun3,4; Kou, Qunhuan3,4; Li, Hongyuan3,4; Cao, Yangzhi3,4; Chen, Meng3,4; Meng, Xin4; Zhang, Yinyong3,4; Wang, Ting2; Wang, Hui1; Zhang, Dan4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-04-10
页码21
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00265
通讯作者Zhang, Dan(zhangdan3@simm.ac.cn) ; Yang, Yushe(ysyang@simm.ac.cn)
英文摘要Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.
WOS关键词DRUG-DELIVERY ; PSEUDOMONAS-AERUGINOSA ; ESCHERICHIA-COLI ; IRON ACQUISITION ; SIDEROPHORES ; CEPHALOSPORIN ; TRANSPORT ; ALBOMYCIN ; PROTEIN ; ANTIBIOTICS
资助项目Youth Innovation Promotion Association of the Chinese Academy of Scienc[2021275]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001200238300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310771]  
专题新药研究国家重点实验室
通讯作者Zhang, Dan; Yang, Yushe
作者单位1.China Pharmaceut Univ, Nanjing 211198, Jiangsu, Peoples R China
2.Sichuan Primed Biotech Grp Co Ltd, Dept Microbiol, Chengdu 610041, Sichuan, Peoples R China
3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Fangjun,Kou, Qunhuan,Li, Hongyuan,et al. Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:21.
APA Liu, Fangjun.,Kou, Qunhuan.,Li, Hongyuan.,Cao, Yangzhi.,Chen, Meng.,...&Yang, Yushe.(2024).Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria.JOURNAL OF MEDICINAL CHEMISTRY,21.
MLA Liu, Fangjun,et al."Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria".JOURNAL OF MEDICINAL CHEMISTRY (2024):21.

入库方式： OAI收割

来源：上海药物研究所

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