Discovery of Conformationally Constrained Dihydro Benzo-Indole Derivatives as Metallo-β-Lactamase Inhibitors to Tackle Multidrug-Resistant Bacterial Infections

The discovery of metallo-β-lactamase (MBL) inhibitors is crucial in the fight against bacterial infections following the emergence and rapid spread of New Delhi metallo-β-lactamase-1 (NDM-1), as well as clinically relevant Verona integrin-encoded metallo-β-lactamase (VIM), and Imipenemase (IMP). The situation is alarming as there are insufficient antibiotics in the pipeline to combat critical multidrug-resistant infections. Here, we report the discovery of novel dihydrobenzo-indole (dBI) derivatives as a new class of potent metallo-β-lactamase inhibitors (MBLIs) by applying scaffold hopping, conformation constrained, and substituent-decorating strategies. Among them, compound 17u exhibited the best inhibitory activity against MBL with acceptable physicochemical and ADME properties. 17u exhibited remarkable enhancement of carbapenems' effectiveness against a range of MBL-producing clinical strains. This efficacy extended to in vivo settings when combined with the imipenem antibiotic, significantly reducing the bacterial load in a thigh infection model. Consequently, it qualifies as a prime candidate for further development as an MBLI.