Sustainable Joullié–Ugi and Continuous Flow Implementation Led to Novel Captopril-Inspired Broad-Spectrum Metallo-β-Lactamase Inhibitors
Metallo-β-lactamases (MBL) production is one of the most alarming bacterial resistance mechanisms, conferring broad-spectrum resistance to most β-lactam antibiotics and combinations with β-lactamase inhibitors. Since no MBL inhibitors have been approved yet, the quest for novel, safe, and effective compounds, possibly endowed with broad-spectrum activity against clinically relevant MBLs, represents an urgent clinical need. Inspired by captopril, which behaves as a weak MBL inhibitor, we herein report a continuous flow protocol for the generation of new MBL inhibitors. We employed a Joullié-Ugi multicomponent reaction for generating two indoline-based subseries, reproducing the captopril binding mode, while increasing the hydrophobic interactions within the MBL active site. Interaction between inhibitors and five clinically relevant MBL isoforms (NDM-1, VIM-1, VIM-2, IMP-1, and IMP-7) was investigated by biochemical methods and rationalized through docking studies. Furthermore, the activity in clinical isolates in synergy with β-lactam antibiotics was assessed, thus paving the way to a further optimization campaign.
Authors
- Ewgenij Proschak (ORCID: https://orcid.org/0000-0003-1961-1859)
- Simona Barone (ORCID: https://orcid.org/0000-0003-3592-7028)
- Steffen Brunst
- Daniele Tedesco (ORCID: https://orcid.org/0000-0003-2585-7791)
- Jean‐Denis Docquier (ORCID: https://orcid.org/0000-0001-9483-4476)
- Vincenzo Summa (ORCID: https://orcid.org/0000-0002-6288-2681)
- E Cassese
- M Rotter
- Thomas A. Wichelhaus (ORCID: https://orcid.org/0000-0002-4029-2955)
- Mattia Mori (ORCID: https://orcid.org/0000-0003-2398-1254)
- Sveva Pelliccia (ORCID: https://orcid.org/0000-0002-5526-5554)
- Margherita Brindisi (ORCID: https://orcid.org/0000-0001-9119-3773)
- Antonella Ilenia Alfano (ORCID: https://orcid.org/0000-0003-0908-037X)
- Pasquale Russomanno (ORCID: https://orcid.org/0000-0002-0236-1200)
- Lilia Weizel (ORCID: https://orcid.org/0000-0002-0373-2114)
- Sacha Cancade
- Luigi Cutarella (ORCID: https://orcid.org/0009-0004-9789-8060)
- Denia Frank (ORCID: https://orcid.org/0000-0002-3433-504X)
- Valerio Baia
- Nicolò Messano
Institutions
- University of Siena (IT)
- Goethe University Frankfurt (DE)
- Federico II University Hospital (IT)
- Institute of Organic Synthesis and Photoreactivity (IT)
- University Hospital Frankfurt (DE)
- Interuniversity Consortium for Magnetic Resonance (IT)
- National Research Council (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00750
- Citations
- 1
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 0.59
Funders
- Ministero dell'Università e della Ricerca