Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
文献类型：期刊论文
| 作者 | Tan, Liang2,3; Tao, Yunliang4; Wang, Ting1; Zou, Feng1; Zhang, Shuhua1; Kou, Qunhuan2,3; Niu, Ao5; Chen, Qian2,3; Chu, Wenjing2,3; Chen, Xiaoyan2,3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2017-04-13 |
| 卷号 | 60期号:7页码:2669-2684 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6b01261 |
| 文献子类 | Article |
| 英文摘要 | Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens. |
| WOS关键词 | BETA-LACTAM ANTIBIOTICS ; MICROBIAL IRON TRANSPORT ; DRUG-DELIVERY AGENTS ; PSEUDOMONAS-AERUGINOSA ; ANTIBACTERIAL ACTIVITY ; BACTERIAL-INFECTIONS ; MONOBACTAMS ; CEPHALOSPORINS ; SIDEROPHORES ; MONOCARBAMS |
| 资助项目 | National Natural Science Foundation of China[81573284] ; National Science and Technology Major Project of China[2014ZX09507009-013] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000399436100005 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272700]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Wang, Haidong; Yang, Yushe |
| 作者单位 | 1.Sichuan Primed Biotech Grp Co Ltd, Dept Microbiol, Chengdu 610041, Sichuan Provinc, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Jiaxing Univ, Coll Biol Chem Sci & Engn, Jiaxing 314001, Zhejiang, Peoples R China; 5.China Pharmaceut Univ, Sch Pharm, Dept Pharmacol, Nanjing 210009, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tan, Liang,Tao, Yunliang,Wang, Ting,et al. Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(7):2669-2684. |
| APA | Tan, Liang.,Tao, Yunliang.,Wang, Ting.,Zou, Feng.,Zhang, Shuhua.,...&Yang, Yushe.(2017).Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections.JOURNAL OF MEDICINAL CHEMISTRY,60(7),2669-2684. |
| MLA | Tan, Liang,et al."Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections".JOURNAL OF MEDICINAL CHEMISTRY 60.7(2017):2669-2684. |
入库方式： OAI收割
来源：上海药物研究所
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