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

• Published in: Tetrahedron 2019-03, Vol.75 (11), p.1525-1540
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antibiotic adjuvant; Bacteriology; Chemical Sciences; Chemistry: 440; Dipicolylamine derivatives; Kjemi: 440; Life Sciences; Matematikk og Naturvitenskap: 400; Mathematics and natural science: 400; MBL-producing gram negative bacteria; Medicinal Chemistry; Microbiology and Parasitology; Multidrug resistant bacteria; Organic chemistry; VDP; Zinc chelators
• ISSN: 0040-4020; 1464-5416; 1464-5416
• DOI: 10.1016/j.tet.2019.02.004

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. [Display omitted]