Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
| العنوان: | Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries |
|---|---|
| المؤلفون: | Michael Spaargaren, K. Barry Sharpless, Moreno Galleni, S. Adrian Saldanha, Patricia Lassaux, Timothy P. Spicer, Peter Hodder, Prem S. Subramaniam, Joseph R. Fotsing, Timo Weide, Carine Bebrone, Dmitriy Minond, Valery V. Fokin |
| المصدر: | Bioorganic & Medicinal Chemistry. 17:5027-5037 |
| بيانات النشر: | Elsevier BV, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Models, Molecular, Molecular model, Stereochemistry, High-throughput screening, p-Chloromercuribenzoic Acid, Clinical Biochemistry, Pharmaceutical Science, Microbial Sensitivity Tests, Biochemistry, beta-Lactamases, Article, Small Molecule Libraries, Catalytic Domain, Drug Discovery, Escherichia coli, Enzyme Inhibitors, Molecular Biology, Beta-Lactamase Inhibitors, Antibacterial agent, chemistry.chemical_classification, Analgesics, Organic Chemistry, Drug Synergism, bacterial infections and mycoses, Small molecule, Combinatorial chemistry, Anti-Bacterial Agents, Imipenem, Enzyme, chemistry, Click chemistry, Molecular Medicine, Mitoxantrone, beta-Lactamase Inhibitors, Protein Binding |
| الوصف: | VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K(i) and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays. |
| تدمد: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2009.05.070 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e20c29e7320018d33d62c0290c7abe2f https://doi.org/10.1016/j.bmc.2009.05.070 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e20c29e7320018d33d62c0290c7abe2f |
| قاعدة البيانات: | OpenAIRE |
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