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Title: The synthesis of imidazo[1,2-a]pyrazines as inhibitors of the VirB11 ATPase and their incorporation into bivalent compounds
Author: Sayer, J. R.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Helicobacter pylori are gram negative bacteria that colonise in the human stomach causing illnesses such as peptide ulcers and various cancers. Through targeting a component of their secretion apparatus, it is envisaged that translocation of toxic molecules will be inhibited and therefore virulence would be reduced. Virtual high throughput screening of the Helicobacter pylori VirB11 ATPase, HP0525, identified imidazo[1,2-a]pyrazine compounds as potential ATP mimics and ATPase inhibitors. Synthesis of these target compounds was carried out, with two routes established to deliver 2- and 3- aryl regioisomers. In vitro screening identified compound 14 as the lead compound (IC50 = 7 μM) and studies have shown it to be a competitive inhibitor of ATP. Based upon in silico interactions of this compound within the ATP binding site, a second generation of compounds were then designed and synthesised. Whilst these compounds showed no major improvements in potency, two further inhibitors were identified as potential leads. Trends in the structure-activity-relationship of these imidazo[1,2- a]pyrazine compounds have also been identified, paving the way for the design of further novel compounds. In addition, the lead compound 14 was successfully incorporated into peptide-small molecule bivalent compounds. The objective of the peptide moiety was to disrupt hexamer formation of the VirB11 ATPase, whilst the small molecule targets the enzyme active site. Initial studies have shown this class of bivalent compound not to inhibit below 500 μM. Further investigation of these bivalent compounds will be required. Presented in this thesis are details of the synthesis, biological testing and computational evaluation of imidazo[1,2-a]pyrazines and their incorporation into the synthesis of bivalent compounds.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available