Simplified captopril analogues as NDM-1 inhibitors |
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| Institution: | 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;2. High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China;1. Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine;2. Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, 1 Murmanska, Kyiv 02660, Ukraine;3. Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine;4. Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation;1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia;2. National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia;3. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia;4. Centre de Recherche des Cordeliers, LRMA, Equipe 12, Université Pierre et Marie Curie, Paris 6, UMR S 872, Paris F-75006 France;5. INSERM, U872, Paris F-75006 France;6. Université Paris Descartes, Sorbonne Paris Cité, UMR S 872, Paris F-75006 France;7. Institut Parisien de Chimie Moléculaire, équipe GOBS, Université Pierre et Marie Curie, Paris 6, France;8. Centre National de la Recherche Scientifique, UMR 7201, Paris F-75006 France;9. AP-HP, Hôpital Européen Georges Pompidou, Paris F-75015 France;10. Rhode Island Hospital, Brown University, Providence, RI 02903-4923, USA;11. Laboratoire des Enveloppes Bactériennes et Antibiotiques, University Paris-Sud, IBBMC, UMR 8619, 91405 Orsay, France;12. CNRS, 91405 Orsay, France;13. Antimicrobial Research Centre and School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, UK;14. Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia;1. Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292, USA;2. Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, 501 S. Preston St., Louisville, KY 40292, USA |
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| Abstract: | Captopril is a New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9 μM. 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 1.0 μM. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10 μM, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections. |
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| Keywords: | Captopril NDM-1 inhibitor Metalantidote 3-Mercapto-2-methylpropanoic acid |
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