creators_name: Dhiman, Pulkit
creators_name: Das, Satyajeet
creators_name: Pathania, Vikas
creators_name: Rawat, Suraj
creators_name: Nandanwar, Hemraj S
creators_name: Thakur, Krishan G
creators_name: Chaudhari, Vinod D
type: article
datestamp: 2026-02-02 07:15:57
lastmod: 2026-02-02 07:15:57
metadata_visibility: show
title: Discovery of conformationally constrained dihydro Benzo-indole derivatives as metallo-β-lactamase inhibitors to tackle multidrug-resistant bacterial infections
abstract: 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.
date: 2025-04
publication: J. Med. Chem.
volume: 68
number: 7
publisher: American Chemical Society (ACS)
pagerange: 7062-7081
citation:   Dhiman, Pulkit and Das, Satyajeet and Pathania, Vikas and Rawat, Suraj and Nandanwar, Hemraj S and Thakur, Krishan G and Chaudhari, Vinod D  (2025) Discovery of conformationally constrained dihydro Benzo-indole derivatives as metallo-β-lactamase inhibitors to tackle multidrug-resistant bacterial infections.  J. Med. Chem., 68 (7).  pp. 7062-7081.