Simplified captopril analogues as NDM-1 inhibitors

Ningning Li; Yintong Xu; Qiang Xia; Cuigai Bai; Taiyi Wang; Lei Wang; Dingdi He; Nannan Xie; Lixin Li; Jing Wang; Hong-Gang Zhou; Feng Xu; Cheng Yang; Quan Zhang; Zheng Yin; Yu Guo; Yue Chen

doi:10.1016/j.bmcl.2013.10.068

Simplified captopril analogues as NDM-1 inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):386-9. doi: 10.1016/j.bmcl.2013.10.068. Epub 2013 Nov 6.

Authors

Ningning Li¹, Yintong Xu¹, Qiang Xia¹, Cuigai Bai², Taiyi Wang¹, Lei Wang¹, Dingdi He¹, Nannan Xie¹, Lixin Li², Jing Wang², Hong-Gang Zhou¹, Feng Xu¹, Cheng Yang¹, Quan Zhang³, Zheng Yin⁴, Yu Guo⁵, Yue Chen⁶

Affiliations

¹ 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.
² High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 24269122
DOI: 10.1016/j.bmcl.2013.10.068

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.

Keywords: 3-Mercapto-2-methylpropanoic acid; Captopril; Metalantidote; NDM-1 inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Captopril / chemical synthesis
Captopril / chemistry
Captopril / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Structure
Structure-Activity Relationship
beta-Lactamase Inhibitors*
beta-Lactamases / metabolism

Substances

Enzyme Inhibitors
beta-Lactamase Inhibitors
Captopril
beta-Lactamases
beta-lactamase NDM-1