Design and synthesis of novel synthetic and natural product inspired trypanosomatid inhibitors

Abstract

Chapter 1 – Introduction of neglected tropical diseases, their impact in our society, treatments, and current challenges. We further explore how a limited understanding of these diseases impedes their treatments. Identification of novel compounds and targets as well as repurposing of previously developed promising drug candidates, may lead to improvement of current treatments methods.

Chapter 2 – Nitro heteroaromatic compounds have demonstrated their potential through their recurrent use as antiparasitic treatments. The novel series of nitro containing heteroaromatics moieties presented in this work were designed to further explore their antiparasitic potential and improve the series for the use in target identification studies.

Chapter 3 – Fumagillin, a natural product isolated from Aspergillus fumigatus, has recently been found to be a promising antiparasitic drug candidate. Its target in mammalian cell lines has been found to be the enzyme MetAP2, however its target in trypanosomatids parasite is yet to be confirmed. In this chapter, we discuss the development of a new series of fumagillin analogues with increased antiparasitic potential. The determined SAR is further applied in the synthesis of probes for imaging and photo-affinity labelling suitable for target identification.

Chapter 4 – Summary of the synthesised compounds for both series and biological data obtained throughout this work, and discussion of further work on both series towards novel analogues with antiparasitic potential.