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.