Poster Presentation RACI Biomolecular Division Conference 2013

2-N-Acyl-4-cyanopyrroles as Inhibitors of the IMP-1 Metallo-β-lactamase (MBL) (#92)

Daniel T. C. Tan 1 , Gerhard Schenk 1 , Ross P. McGeary 1
  1. University of Queensland, St Lucia, Qld, Australia

β-Lactam antibiotic resistance caused by metallo-β-lactamases (MBLs) is an emerging health threat to humans. These zinc-dependent lactamases are capable of hydrolysing a wide spectrum of β-lactam antibiotics. No clinical inhibitors of MBLs are available.1  The clinically-relevant IMP-1 MBL is a suitable enzyme target for undertaking inhibitory activity studies.2  As part of our on-going work to develop novel MBL inhibitors we have identified a 2-amino-4-cyanopyrrole (1) as a competitive IMP-1 inhibitor with a Ki value of 21 μM.3  Synthetic modification of pyrrole (1) led to the identification of a series of 2-N-acyl substituted pyrrole derivatives which exhibited improved IMP-1 inhibitory activities with some Ki values as low as 1.24 μM.

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  1. Bebrone, C., Metallo-β-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochemical Pharmacology 2007, 74 (12), 1686-1701.
  2. Vella, P.; Hussein, W. M.; Leung, E. W. W.; Clayton, D.; Ollis, D. L.; Mitić, N.; Schenk, G.; McGeary, R. P., The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening. Bioorganic & Medicinal Chemistry Letters 2011, 21 (11), 3282-3285.
  3. Hussein, W. M.; Fatahala, S. S.; Mohamed, Z. M.; McGeary, R. P.; Schenk, G.; Ollis, D. L.; Mohamed, M. S., Synthesis and Kinetic Testing of Tetrahydropyrimidine-2-thione and Pyrrole Derivatives as Inhibitors of the Metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chemical Biology & Drug Design 2012, 80 (4), 500-515.