Structure-Based Discovery and Synthesis of Pyrrolo[2,1-c][1,4]-benzodiazepine Derivatives as Non-β-lactam Serine β-lactamase Inhibitors

The rapid emergence of antimicrobial resistance has threatened the efficacy of first-line antibiotic therapeutics and presents health care systems with serious challenges. There is an urgent need to design and develop both additional therapeutic alternatives and enhanced antibacterial stewardship. Production and dissemination of β-lactamases as the major cause of bacterial resistance to β-lactam antibiotics initiates the catalytic hydrolysis and therefore, inactivates the β-lactams. A program was initiated to discover a series of novel non-β-lactam inhibitors containing 7-membered ring dilactam scaffolds to explore potent inhibitors of serine β-lactamases. All designed compounds 1-13 passed the Lipinski’s rule of five test which is used to identify potential drug-like compounds and were docked into the active site of TEM-1 β-lactamase using ParDOCK software. Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives 1-7 were synthesized and the association of ligands with purified enzymes in solution was examined. The competitive enzyme inhibition kinetics results have shown that PBDs are quite weak inhibitors when tested against TEM-1 and P99. The limited inhibitory activity of the compounds 1-7 was assumed to happen due to the lack of solubility and bulky nature of the molecules, thus limiting the optimal ligand-enzyme interactions. Analogs 11-13 were further synthesized to reduce the steric hindrance of the PBDs while promoting the electrophilicity of the active lactam. Compounds 8-13 were also exhibited low inhibitory activity against both enzymes.


Joseph O Osazee, Joel K Annor-Gymafi, Carla Slebodnick and Abbas G Shilabin*

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