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.