%0 Journal Article
%A Dhiman, Pulkit
%A Das, Satyajeet
%A Pathania, Vikas
%A Rawat, Suraj
%A Nandanwar, Hemraj S
%A Thakur, Krishan G
%A Chaudhari, Vinod D
%D 2025
%F open:3218
%I American Chemical Society (ACS)
%J J. Med. Chem.
%N 7
%P 7062-7081
%T Discovery of conformationally constrained dihydro Benzo-indole derivatives as metallo-β-lactamase inhibitors to tackle multidrug-resistant bacterial infections
%U http://crdd.osdd.net/open/3218/
%V 68
%X 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.