Optimisation of lead inhibitors of the imipenemase 1 (IMP-1) metallo-β-lactamase enzyme

Tan, Daniel Teoh Chuan (2016). Optimisation of lead inhibitors of the imipenemase 1 (IMP-1) metallo-β-lactamase enzyme PhD Thesis, School of Chemistry and Molecular Biosciences, The University of Queensland. doi:10.14264/uql.2016.371

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Author Tan, Daniel Teoh Chuan
Thesis Title Optimisation of lead inhibitors of the imipenemase 1 (IMP-1) metallo-β-lactamase enzyme
School, Centre or Institute School of Chemistry and Molecular Biosciences
Institution The University of Queensland
DOI 10.14264/uql.2016.371
Publication date 2016-06-20
Thesis type PhD Thesis
Supervisor Ross McGeary
Gerhard Schenk
Total pages 254
Language eng
Subjects 0305 Organic Chemistry
0304 Medicinal and Biomolecular Chemistry
Formatted abstract
β-Lactam antibiotics such as penicillin G (1) account for more than 50% of the world’s antibiotics prescribed. These chemical agents work by disrupting bacterial cell wall synthesis. Over-prescription of β-lactam antibiotics has led to bacterial resistance in the form of β-lactamase expression. β-Lactamases, or β-lactam degrading enzymes, can be divided into four classes, A, B, C and D. The class B β-lactamases are the zinc-dependent enzymes, and are thus known as the metallo-β-lactamases (MBLs). Of particular concern are the MBLs, particularly the B1 MBLs, such as Imipenemase 1 (IMP-1), which can be spread by horizontal gene transfer. To date there are no known clinical inhibitors against MBLs.

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This thesis explores the optimisation of two classes of IMP-1 lead compounds, 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (65) and (2RS, 4R)-2-phenylthiazolidine-4-carboxylic acid (120a).

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The structure-activity-relationship (SAR) study of pyrrole 65 led to the successful identification of two potent IMP-1 inhibitors, 93 and 99, with a 14- to 17-fold increase in IMP-1 inhibitory potency as compared to pyrrole 65. However, synthetic modification of the 3-carbonitrile group of 65, or deletion of the N-benzyl chain resulted in a significant loss of IMP-1 inhibitory activity.

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The SAR study of thiazolidine 120a resulted in the discovery of the mercapto-amide-linked thiazolidine, 124a with a 20-fold improvement in IMP-1 inhibitory activity as compared to 120a. The extension of this study led to the identification of a highly potent thiazolidine derivative, 124g with IMP-1 inhibitory potency in the sub-micromolar range.

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Keyword β-lactam
Antibiotic Resistance
Computational modelling
Structure activity relationship

Document type: Thesis
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Created: Sat, 04 Jun 2016, 12:56:46 EST by Daniel Tan on behalf of Learning and Research Services (UQ Library)