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dc.contributor.authorSveiczer, Attila
dc.description.abstractThis thesis reports two projects aimed at addressing challenges within fragment-based drug discovery. The first project describes efforts towards utilising synthetic methodology to address deficiencies within fragment screening collections. This involved the development of a modular, robust and scalable route to access α,α-disubstituted amino ester building blocks, which in turn were derivatised to allow the rapid assembly of five (a total of eight in collaboration) spirocyclic scaffolds. Importantly, this library was structurally diverse, comprising three (a total of six in collaboration) pharmacophore-like heterocycles and carbocycles. Moreover, numerous three-dimensional exit vectors were incorporated within each core spirocycle, and the ability of these handles to effect a diverse set of chemical modifications was exemplified through the generation of 16 (a total of 21 in collaboration) examples. Computational studies highlighted the excellent physicochemical and 3D properties of the library, as well as the broad coverage of underexplored chemical space that was achieved. This library was also screened for antibacterial activity in a phenotypic assay against the clinically relevant bacterial strains, Pseudomonas aeruginosa and Staphylococcus aureus. The second project examined the inhibition of propionate detoxification mechanisms in bacteria as an attractive strategy for the development of antibacterial agents. A fragment screening campaign against 2-methylcitrate synthase (PrpC) from Pseudomonas aeruginosa identified several hit compounds based on an indole unit. Synthetic efforts were undertaken to elaborate these fragment hits to increase potency. The adopted strategy focused on growing the indole fragment towards the nearby oxaloacetate binding pocket and occupying it with a fragment mimicking its natural substrate. This approach yielded a compound with an in vitro half maximal inhibitory concentration of 130 µM against the enzymatic activity of PrpC.
dc.rightsAll Rights Reserved
dc.subjectorganic chemistry
dc.subjectsynthetic chemistry
dc.subjectfragment-based drug discovery
dc.subjectfragment library
dc.subjectthree-dimensional fragment
dc.subjectfragment linking
dc.subjectpseudomonas aeruginosa
dc.subjectmolecular biology
dc.titleStudies within Fragment-Based Drug Discovery: Library Synthesis and Hit-to-Lead Optimisation
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.type.qualificationtitlePhD in Chemistry
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/P020291/1)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/E52891X/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/J016012/1)
pubs.funder-project-idEuropean Research Council (279337)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/R005435/1)
cam.supervisorSpring, David R
cam.supervisorWelch, Martin
cam.supervisor.orcidSpring, David [0000-0001-7355-2824]
cam.supervisor.orcidWelch, Martin [0000-0003-3646-1733]

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