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dc.contributor.advisorFlorence, Gordon John
dc.contributor.authorFraser, Andrew Logan
dc.coverage.spatialxviii, 379 p. : ill. (some col.), chartsen_US
dc.description.abstractIn 2010 the Florence group completed the total synthesis of the natural product chamuvarinin which, in collaboration with the Smith group, was found to be a potent inhibitor of the pathogenic parasite T. brucei. Several simplified analogues were found to maintain this inhibitory activity alongside activity against the related species T. cruzi and L. major. The mechanism of action and structural features of these compounds responsible for the observed biological activity remained elusive despite a large synthetic effort by the Florence group. With the aim of identifying protein targets in trypanosomatids to understand the mechanism of action, several photo-affinity labeling analogs have been successfully synthesised and utilised to identify a primary protein target. This protein target was fully validated and molecule docking to this protein was evaluated in-silico. This computational data was used to evaluate the mode of action and aided in the design of simplified compounds which were found to maintain the previously observed anti-parasitic activity but with decreased toxicity to mammalian cells alongside decreased synthetic complexity. The total synthesis of the natural product ascr#18 is also described alongside the synthesis of photo-affinity labeling analogs. This natural product is implicated in the modulation of pathogen resistance in plants and has potential application in crop production.en_US
dc.publisherUniversity of St Andrews
dc.subject.lcshAntiparasitic agents--Designen
dc.subject.lcshNatural productsen
dc.titleTarget elucidation of novel trypanosomatid inhibitorsen_US
dc.contributor.sponsorLeverhulme Trusten_US
dc.contributor.sponsorEngineering and Physical Sciences Research Council (EPSRC)en_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.rights.embargoreasonThesis restricted in accordance with University regulations. Print copy restricted until 9th March 2020. Electronic copy restricted until 9th March 2021en

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