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dc.contributor.authorMcConnell, Brendan Neil
dc.date.accessioned2019-03-06T09:36:41Z
dc.date.available2019-03-06T09:36:41Z
dc.date.issued2019-05-18
dc.date.submitted2018-08-22
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290255
dc.description.abstractTuberculosis affects millions of people worldwide every year. The current treatment for TB is divided into a regimen of both first- and second-line drugs, where first-line treatments are more tolerated and require shorter treatment lengths. With rising levels of resistance, alternative treatment regimes are urgently needed to fight this disease. Ethionamide, a second-line drug is administered as a prodrug which is activated in vivo by the enzyme EthA, which is in turn regulated by EthR. The disruption of the action of EthR could lead to novel therapeutics which could enhance the efficacy of ethionamide, and raise it to a first-line treatment. The work reported in this thesis examines the elaboration of three chemical scaffolds using fragment-based approaches to develop novel inhibitors capable of disrupting the EthR-DNA interaction. The first scaffold, 5-(furan-2-yl)isoxazole was investigated by fragment-merging approaches and produced compounds with the best of these having a KD of 7.4 uM. The second scaffold, an aryl sulfone was elaborated using fragment-merging strategies. This led to several modifications of the fragment, leading to several variants with KDs around 20 uM. With both of these series the affinity could not be improved below 10 uM and due to the synthetic complexity a further scaffold was prioritised. The third scaffold was explored was a 4-(4-(trifluoromethyl)phenyl)piperazine using fragmentgrowing from the NH of the piperazine to probe deeper into the EthR binding pocket. In addition to this, SAR around the 4-(trifluoromethyl)phenyl group was assessed to explore the interactions with EthR. These modifications led to compounds with nanomolar IC50s. A range of compounds were then screened by REMAssay to determine the boosting effect on ethionamide, and this identified compounds with up to 30 times boosting in the ethionamide MIC. The final chapter examines a concept where compounds were designed to exploit the dimeric nature of EthR by linking two chemical warheads with a flexible linker. These compounds are examined using mass spectrometry to investigate the stoichiometry of the interaction to provide insight into the binding of these extended compounds and exploring an alternative strategy to inhibit EthR. The work in this thesis demonstrated the successful use of fragment-based approaches for development of novel EthR inhibitors which showed significant ethionamide boosting effects.
dc.description.sponsorshipCambridge Commonwealth, European and International Trust (Poynton Cambridge Australia Scholarship) Cambridge Philosophical Society Access to Learning Fund
dc.language.isoen
dc.rightsAll rights reserved
dc.subjectEthR
dc.subjecttuberculosis
dc.subjectethionamide
dc.subjectTB
dc.subjectfragment-based drug design
dc.subjectFBDD
dc.subjectfragment-based ligand design
dc.subjectFBLD
dc.subjectisothermal titration calorimetry
dc.subjectITC
dc.subjectthermal shift
dc.subjectdifferential scanning fluorimetry
dc.subjectDSF
dc.subjectsurface plasmon resonance
dc.subjectSPR
dc.subjectsulfone
dc.subjectpiperazine
dc.titleFragment-based approaches to targeting EthR from mycobacterium tuberculosis
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentChemistry
dc.date.updated2019-02-06T11:48:56Z
dc.identifier.doi10.17863/CAM.37485
dc.contributor.orcidMcConnell, Brendan Neil [0000-0001-9002-9808]
dc.publisher.collegeWolfson
dc.type.qualificationtitlePh.D. in Chemistry
cam.supervisorAbell, Christopher
cam.thesis.fundingfalse
rioxxterms.freetoread.startdate2020-03-06


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