Year

2019

Degree Name

Doctorate of Philosophy

Department

School of Chemistry and Molecular Bioscience

Abstract

The development of new chemical reactions is equally as important as the applications of the resulting products, which is often the development of medicinal agents. The two parts of the work disclosed herein explore synthetic chemistry from each of these angles. Part I of this work has involved the design and synthesis of novel drug compounds for African sleeping sickness, Chagas disease and leishmaniasis, which are neglected tropical diseases caused by the respective trypanosomal parasites T. brucei, T. cruzi and Leishmania. These diseases call for rapid methods of drug discovery such as drug repurposing and high-throughput screening, and the latter strategy has previously identified WEHI-0086109 (14a) as an anti-T. brucei agent (IC50/SI = 2.50 μM/48). In this work, structure-activity relationships of 14a were established, with an attention to physiochemical properties (MW, ClogP, H-bonding). Many of the resulting novel benzothiazolyl-thiophenamides exhibited antitrypanosomal activity (up to IC50 = 0.32 μM) and selectivity (up to SI > 130) against the surrogate species, T. b. brucei. The derivative 32b was found to surpass 14a when subjected to the human infective species, T. b. rhodesiense (IC50/SI = 5.04 μM/13, 32b vs. 8.96 μM/3, 14a) and deemed suitable for further development, informed by the newly-established structure-activity information. In regard to Chagas disease and leishmaniasis, the existing antiparasitic drug nitazoxanide was identified as a suitable candidate for repurposing, given its known activity against T. cruzi and leishmania. A series of ferrocenyl and cymantrenyl derivatives of nitazoxanide were designed, considering the well-established power of organometallic moieties to exert antiparasitic action via production of reactive oxygen species. Two ferrocenyl derivatives, 56a and 65a, were the first of a novel class of organometallic drug compounds to be synthesised. Though these were found to be inactive against both species of trypanosome, it was proposed that the cymantrenyl derivatives are worth pursuing as antileishmanial agents in the future due to their comparative electron-withdrawing character.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.