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Fluorinated captopr...
Fluorinated captopril analogues inhibit metallo-ll-lactamases and facilitate structure determination of NDM-1 binding pose
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- Kondratieva, Alexandra (författare)
- UiT Arctic Univ Norway, Dept Chem, NO-9037 Tromso, Norway.
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- Palica, Katarzyna, 1992- (författare)
- Uppsala universitet,Organisk kemi
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- Frohlich, Christopher (författare)
- UiT Arctic Univ Norway, Dept Pharm, NO-9037 Tromso, Norway.
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- Hovd, Rebekka Rolfsnes (författare)
- AdjuTec Pharm, NO-0165 Oslo, Norway.
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- Leiros, Hanna-Kirsti S. (författare)
- UiT Arctic Univ Norway, Dept Chem, NO-9037 Tromso, Norway.
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- Erdélyi, Máté, 1975- (författare)
- Uppsala universitet,Organisk kemi
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- Bayer, Annette (författare)
- UiT Arctic Univ Norway, Dept Chem, NO-9037 Tromso, Norway.
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UiT Arctic Univ Norway, Dept Chem, NO-9037 Tromso, Norway Organisk kemi (creator_code:org_t)
- Elsevier, 2024
- 2024
- Engelska.
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 266
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Bacterial resistance to the majority of clinically used ll-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-ll-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding. The new compounds showed activity comparable to the non-fluorinated inhibitors against the New Delhi Metallo-ll-lactamase-1 (NDM-1). The most active compound, a derivative of D-captopril, exhibited an IC50 value of 0.3 mu M. Several compounds demonstrated synergistic effects, restoring the effect of meropenem and reducing the minimum inhibitory concentration (MIC) values in NDM-1 (up to 64-fold), VIM-2 (up to 8-fold) and IMP-26 (up to 8-fold) harbouring Escherichia coli. NMR spectroscopy and molecular docking of one representative inhibitor determined the binding pose in NDM-1, demonstrating that fluorinated analogues of inhibitors are a valuable tool for structural studies of MBL-inhibitor complexes.
Ämnesord
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Metallo-ll-lactamases
- NDM-1
- Inhibitors
- Thiols
- NMR binding -studies
- VIM-2
- IMP-26
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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