title: Simplified captopril analogues as NDM-1 inhibitors.
abstract: Captopril is a New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9μM. It is composed of two units: a 3-mercapto-2-methylpropanoyl fragment and a proline residue. In this study, we synthesized simple amide derivatives of 3-mercapto-2-methylpropanoic acid, and then tested them as NDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition. We found that the lead compound 22 had an IC50 value of 1.0μM. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10μM, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections.
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Li
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Yintong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Cuigai
authors.initials: C
authors.lastname: Bai
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Taiyi
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Dingdi
authors.initials: D
authors.lastname: He
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Xie
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Zhou
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China. Electronic address: zheng_yin@nankai.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China. Electronic address: guoyu@nankai.edu.cn.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: College of Pharmacy and the State Key Laboratory of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China. Electronic address: yuechen@nankai.edu.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D002216:Captopril / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D002216:Captopril; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
keywords: 3-Mercapto-2-methylpropanoic acid; Captopril; Metalantidote; NDM-1 inhibitor