Illudine, a novel potent trypanocidal natural product; optimisation of simplified analogues, investigating its mode of action and elucidation of its p

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The parasitic protozoa Trypanosoma brucei, Trypanosoma cruzi, and Leishmania speciesare the causative agents of the "neglected" tropical diseases: African sleeping sickness,Chagas' disease and leishmaniasis. Collectively, these diseases affect millions of peopleand represent a huge percentage of the world's communicable disease burden. Currentdrug treatments are woefully inadequate, having problems of toxicity, difficult administration in the field, cost and emerging resistance. There is an urgent need for identification of novel therapeutic targets, allowing development of lead compounds into safe, cheap, and easy to administer drugs if these diseases are to be eradicated/controlled; a WHO priority by 2020.Natural products arise from the evolution of organisms to produce secondary metabolites, which enhance the survival and competitiveness of the organism in its habitat. These chemical entities are often complex, structurally diverse, and already biologically validated by their very nature making them ideal starting points for drug candidates. Historically, natural products have proved to be a bountiful resource of lead compounds in drug discovery, with almost 50% of all approved drugs between 1981 and 2011 being natural products themselves or derivatives thereof. Natural products and natural product-like scaffolds, and the typical complexity and diversity that accompanies them, are vastly underrepresented in synthetic libraries, mainly due to their challenging synthesis and enormous difficulty of structural modifications. It has, however, been shown that there is significant positive correlation of greater complexity and incorporation of stereogenic centres, with the transitioning of compounds from discovery, through clinical trials and eventually to drugs. Utilising the inspiration of natural products, for their structural and functional diversity, and biological validation is a beneficial approach for increasing probability of both biological activity and availability.The Smith group have previously undertaken a screen of NIH Natural Products Collection (120isolated compounds) against all three parasites and came up with several highly potent compounds with EC50 in the low nM range with high selectivity versus mammalian cells.One of these targets was Fumagillin, which has been the subject of research in the Florence and Smith groups to optimize the SAR of simplified targets and identify its protein target(s) in T. brucei.Another potent natural product identified in this screen is Illudine M, a sequiterpene with an Ec50 against T. cruzi of 6.67 nM. The synthesis of which has been studied, along with several natural variants. https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01301This will be the main topic of this studentship to undertake the synthesis of illudine and some simplified analogues allowing subsequent testing against the parasites to obtain some SAR and initial phenotyping. Suitable moieties will be added to the optimized simplified analogues allowing cross-linking and affinity purifications to identify protein targets.If time allows and as a backup several other potent trypanocidal natural product hits will investigated including several cyclopeptide analogues.