Monash University
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Novel heterocyclic inhibitors for human African trypanosomiasis

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posted on 2017-03-02, 01:01 authored by Ferrins, Lori
Human African trypanosomiasis (HAT), more commonly known as African sleeping sickness is caused by the protozoan Trypanosoma brucei. There are two subspecies of the parasite that are responsible for human infection; T.b. rhodesiense and T.b. gambiense. These parasites differ in that T.b. rhodesiense results in an acute infection whilst T.b. gambiense results in a chronic infection. HAT was recently named by the World Health Organisation in a list of 17 of the world’s neglected tropical diseases. HAT affects approximately 10,000 people in the remotest parts of Africa with the disease ultimately affecting the central nervous system, resulting in disrupted sleep patterns, brain damage and eventual death. The current treatments for this disease often involve complex therapeutic regimens, lead to the development of long term health issues, and even death in some patients. Reports of resistance developing to some of these treatment options are also becoming more frequent and as a result new treatments are urgently needed. A whole organism high-throughput screen of 87,296 compounds from the WEHI/Bio21 Stage 1 screening library was conducted against T.b. brucei and led to the identification of a number of new compound series. This thesis describes the synthesis and structure-activity relationships (SAR) around four of these series. The first body of work presented centres around the oxazolopyridines and details the initial SAR studies that were conducted. Whilst an increase in the potency of these analogues was achieved there were limiting physicochemical properties that hindered the progression of the series, namely metabolic stability and solubility. A number of analogues were designed and synthesised that particularly focused on improving the metabolic stability of the series. The pyrazine carboxamides are the next series of compounds to be presented in this thesis. Much of the preliminary SAR had already been explored by previous researchers and a number of limitations were uncovered. Notably the metabolism of the series was rapid and the solubility was limiting. In order to address the solubility issue a number of analogues were designed and synthesised with a greater percentage of sp3 carbons and these results are detailed. A number of analogues of the core pyrazine ring were also envisioned and synthesised in order to further probe the SAR around this series. The pyridyl benzamides were chosen for progression as a result of their highly optimisable structure, despite their low micromolar activity against T.b. brucei. The work presented in this chapter demonstrates a significant boost in the activity of the series, down to low nanomolar inhibition as well as the identification of a related series, the thiazole benzamides. Finally, a discussion around the phenyl thiazoles will be presented. A significant SAR exploration had already been conducted by other researchers and potent inhibitors of T.b. brucei had been identified, though the metabolism of the series was rapid and prevented progression of the series. As such a number changes to the core thiazole were envisioned and synthesised as well as modifications to the ethyl linker. The synthesis and results of this work has been detailed herein.


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Principal supervisor

Jonathan Baell

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Medicinal Chemistry

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Faculty of Pharmacy and Pharmaceutical Sciences

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