Phenotypic screening and functional characterisation of anti-protozoan unnatural products

  • William Robert Toddun Mosedale

Student thesis: Doctoral Thesis (PhD)


Trypanosoma brucei is a vector borne protozoan parasite of the class kinetoplastida and is the causative agent of human African trypanosomiasis (HAT), a neglected tropical disease of sub-Saharan Africa that is fatal if untreated, and is also a causative agent of Nagana, a disease of animals and livestock with great economic importance. Having been at forefront of drug discovery during the pioneering days of modern medicine, the development of new therapeutics has since slowed, and the disease had seen little innovation in treatment since the mid-1900s until the recent introduction of eflornithine and most recently Fexinidazole in 2018. While Fexinidazole has been demonstrated to be effective at treating most cases, the rarer but more aggressive form of the disease caused by T. brucei rhodesiense still requires treatment with the dangerous and dated drug, melarsoprol. This project aims to utilise the tried and tested method of phenotypic screening, in combination with activity directed synthesis to identify novel anti-trypanosomal unnatural products of high therapeutic potential based upon selectivity and potency. This will be in addition to an exploration of a sulfonyl-fluoride based covalent warhead aryl compound library as both a potential therapeutic and a proof of concept for chemical proteomics as a tool for anti-parasitic drug discovery. Selected compounds were characterised using well
established techniques such as microscopy, live / dead assays, and growth curves, in addition to more in-depth analysis of the strongest candidate using quantitative proteomics of a compound resistant cell line. A variety of cellular assays were used to validate the finding of the proteomics and help elucidate the mode of action. Three highly active and selective sulfonyl-fluoride warheads are identified in which preliminary evidence suggests a mode of action associated with the dysregulation of the stable acetylated microtubule cytoskeleton for which the parasites rely on for morphology and replication, as well as an iridium based cationic compound, which disrupts the mitochondria and multiple other essential processes within the parasite including glycolysis and nucleotide metabolism.
Date of Award12 Jun 2024
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorTerry K Smith (Supervisor)


  • Trypanosoma
  • Trypanosoma brucei
  • Phenotypic screening
  • Quantitative proteomics
  • Drug resistance
  • Drug discovery
  • Microscopy
  • Covalent drugs
  • Heteroarenes
  • Kinetoplastids

Access Status

  • Full text embargoed until
  • 26 January 2029

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