2. Academic Validation
  3. Sustainable Joullié-Ugi and Continuous Flow Implementation Led to Novel Captopril-Inspired Broad-Spectrum Metallo-β-Lactamase Inhibitors

Sustainable Joullié-Ugi and Continuous Flow Implementation Led to Novel Captopril-Inspired Broad-Spectrum Metallo-β-Lactamase Inhibitors

  • J Med Chem. 2025 Aug 28;68(16):17236-17257. doi: 10.1021/acs.jmedchem.5c00750.
Antonella Ilenia Alfano 1,  Sveva Pelliccia 1,  Simona Barone 1,  Luigi Cutarella 2,  Sacha Michèle Idriss Cancade 3,  Valerio Baia 1,  Emilia Cassese 1,  Pasquale Russomanno 4,  Nicolò Messano 2,  Denia Frank 5,  Lilia Weizel 6,  Marco J Rotter 6,  Steffen Brunst 6,  Thomas A Wichelhaus 5,  Ewgenij Proschak 6,  Daniele Tedesco 7,  Mattia Mori 2,  Jean Denis Docquier 3,  Vincenzo Summa 1,  Margherita Brindisi 1
Affiliations

Affiliations

  • 1 Department of Pharmacy (Department of Excellence 2023-2027), University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
  • 2 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 3 Department of Medical Biotechnologies, University of Siena, Viale Bracci 16, 53100 Siena, Italy.
  • 4 Magnetic Resonance Centre (CERM), Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP) and Department of Chemistry "Ugo Schiff", University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
  • 5 Goethe University Frankfurt, University Hospital, Institute of Medical Microbiology and Infection Control, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
  • 6 Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany.
  • 7 Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, 40129 Bologna, Italy.
PMID: 40815386 DOI: 10.1021/acs.jmedchem.5c00750
Abstract

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.

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