Targeting Metallo-β-Lactamases:Discovery ofNovel Dihydro-Chromeno Pyrrole (dCPs) Derivatives for Combating Drug-ResistantInfections

Abstract Clinically approved therapies have established that combining β-lactam antibiotics with β-lactamase inhibitors is an effective strategy to counter antibiotic resistance; however, infections caused by metallo-β-lactamase (MBL) producing bacteria remain a critical unmet medical need. Building on our previous efforts targeting clinically relevant MBLs, including New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM), and imipenemase (IMP), we report the design and synthesis of 40 novel dihydro-chromeno-pyrrole (dCP) derivatives using a scaffold-hopping approach. Several compounds displayed potent MBL inhibition and lead compounds 74 and 91 effectively restored the activity of mmeropenem and imipenem against carbapenem-resistant Gram-negative pathogens. Optimization efforts focused on improving ADME properties while maintaining potency, and lead compounds were further evaluated for their pharmacokinetic profiles. Docking studies revealed favorable binding interactions of inhibitors with MBL proteins, supporting and justifying the observed inhibitory activity. Overall, this study provides a robust framework for lead optimization and identifies promising candidates for preclinical development.