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
  • 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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