Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries

Dmitriy Minond, S. Adrian Saldanha, Prem Subramaniam, Michael Spaargaren, Timothy Spicer, Joseph R. Fotsing, Timo Weide, Valery V. Fokin, K. Barry Sharpless, Moreno Galleni, Carine Bebrone, Patricia Lassaux, Peter Hodder

Результат исследований: Материалы для журналаСтатья

39 Цитирования (Scopus)

Аннотация

VIM-2 is an Ambler class B metallo-β-lactamase (MBL) capable of hydrolyzing a broad-spectrum of β-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 Ki 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-anthr acenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (Ki =Ki = 1.5 ± 0.2 μM) 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-iodobenzen esulfonamide (1, Ki = 0.41 ± 0.03 μM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfona mide (2, Ki = 1.4 ± 0.10 μM). 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.

Язык оригиналаАнглийский
Страницы (с-по)5027-5037
Число страниц11
ЖурналBioorganic and Medicinal Chemistry
Том17
Номер выпуска14
DOI
СостояниеОпубликовано - 15 июл 2009
Опубликовано для внешнего пользованияДа

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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  • Цитировать

    Minond, D., Saldanha, S. A., Subramaniam, P., Spaargaren, M., Spicer, T., Fotsing, J. R., Weide, T., Fokin, V. V., Sharpless, K. B., Galleni, M., Bebrone, C., Lassaux, P., & Hodder, P. (2009). Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries. Bioorganic and Medicinal Chemistry, 17(14), 5027-5037. https://doi.org/10.1016/j.bmc.2009.05.070