@article{open3218,
          volume = {68},
          number = {7},
           month = {April},
          author = {Pulkit Dhiman and Satyajeet Das and Vikas Pathania and Suraj Rawat and Hemraj S Nandanwar and Krishan G Thakur and Vinod D Chaudhari},
           title = {Discovery of conformationally constrained dihydro Benzo-indole derivatives as metallo-{\ensuremath{\beta}}-lactamase inhibitors to tackle multidrug-resistant bacterial infections},
       publisher = {American Chemical Society (ACS)},
            year = {2025},
         journal = {J. Med. Chem.},
           pages = {7062--7081},
             url = {http://crdd.osdd.net/open/3218/},
        abstract = {The discovery of metallo-{\ensuremath{\beta}}-lactamase (MBL) inhibitors is crucial in the fight against bacterial infections following the emergence and rapid spread of New Delhi metallo-{\ensuremath{\beta}}-lactamase-1 (NDM-1), as well as clinically relevant Verona integrin-encoded metallo-{\ensuremath{\beta}}-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-{\ensuremath{\beta}}-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.}
}