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Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

Permanent link
https://hdl.handle.net/10037/17889
DOI
https://doi.org/10.1016/j.tet.2019.02.004
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Accepted manuscript version (PDF)
Date
2019-02-02
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Author
Prandina, Anthony; Radix, Sylvie; Le Borgne, Marc; Jordheim, Lars Petter; Bousfiha, Zineb; Fröhlich, Christopher; Leiros, Hanna-Kirsti S.; Samuelsen, Ørjan; Frøvold, Espen; Rongved, Pål; Åstrand, Ove Alexander Høgmoen
Abstract
Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D-Ala-D-Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64 mg/L to 2 and 1–2 mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC50 value of 1i against VIM-2 was 9.8 and 2.2 μM after 5 and 20 min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 μM.
Publisher
Elsevier
Citation
Prandina, A.; Radix, S.; Le Borgne, M.; Jordheim, L.P.; Bousfiha, Z,; Fröhlich, C.F.; Leiros, H.; Samuelsen, Ø.; Frøvold, E.; Rongved, P.R.; Åstrand, O.A.H. (2019) Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors. Tetrahedron, 75, (11), 1525-1540
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