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

Abstract The discovery of pan-metallo-β-lactamase (pan-MBL) inhibitors is crucial in the fight against bacterial infection 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 multi-drug resistant infections. Here, we report the discovery of novel Dihydro Benzo-Indole (dBI) derivatives as a new class of potent pan-metallo-β-lactamase inhibitors (MBLIs) by applying scaffold hopping, conformation constrained, and substituent-decorating strategies. Among them, compound 17u exhibited best inhibitory activity against pan-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 bacterial load in a thigh infection model. Consequently, it qualifies as a prime candidate for further development as a MBLI.