%A Pulkit Dhiman
%A Satyajeet Das
%A Vikas Pathania
%A Suraj Rawat
%A Hemraj S Nandanwar
%A Krishan G Thakur
%A Vinod D Chaudhari
%J J. Med. Chem.
%T Discovery of conformationally constrained dihydro Benzo-indole derivatives as metallo-?-lactamase inhibitors to tackle multidrug-resistant bacterial infections
%X The discovery of metallo-?-lactamase (MBL) inhibitors is crucial in the fight against bacterial infections following the emergence and rapid spread of New Delhi metallo-?-lactamase-1 (NDM-1), as well as clinically relevant Verona integrin-encoded metallo-?-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-?-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.
%N 7
%P 7062-7081
%V 68
%D 2025
%I American Chemical Society (ACS)
%L open3218