|dc.description.abstract||Malaria is a mosquito-borne disease caused by the parasitic protozoan Plasmodium that is
responsible for approximately half a million deaths every year. The vast majority of these
deaths are caused by P. falciparum in Sub-Saharan Africa (SSA). Although most cases of P.
falciparum malaria can currently be treated effectively using artemisinin-based combination
therapies (ACTs), resistance to ACTs is beginning to emerge in South-East Asia. This resistance
is likely to proliferate and spread into SSA, after which a public health catastrophe is likely to
follow. There is currently no drug poised to replace ACTs as the front-line treatment for
malaria and there is a need for the discovery of new drugs. Historically, natural products from
plants have been our best source of anti-malarial drugs: the alkaloid quinine (from the bark of
the Cinchona tree) and the sesquiterpene lactone artemisinin (from the leaves of Artemisia
annua) have formed the backbone of anti-malarial chemotherapeutics for centuries.
The primary goal of this thesis was to respond to the need for new anti-plasmodial
compounds. This was achieved by collecting and screening a library of Australian Rutaceae
species against P. falciparum, selecting species that showed high bioactivity and performing
large-scale natural product purification. Isolated natural products were screened against
chloroquine-resistant and sensitive P. falciparum and human embryonic kidney (HEK-293) cells
to evaluate bioactivity and parasite selectivity. This forms the majority of the thesis (Chapters
Chapter 2 reports the initial collection, screening and fingerprinting of a library of 30 Australian
Rutaceae species. Chemical fingerprinting using LC-MS was used to identify species that were
most likely to contain new natural products. From these results, four species were selected for
investigation: Clausena brevistyla (Chapter 2) Flindersia pimenteliana (Chapters 3-4),
Acronychia pubescens (Chapter 5) and Pitaviaster haplophyllus (Chapter 6). This chapter also
reports the isolation of two known pyranocoumarins from C. brevistyla. One of the
pyranocoumarins showed potent and selective activity against P. falciparum, with IC50 values
between 466 – 822 nM.
Chapter 3 reports the chemical investigation of F. pimenteliana leaf material. From this plant, a
new class of ascorbic-acid adduct indole alkaloids, pimentelamines A-C, were isolated along
with one new indole alkaloid, 2-isoprenyl-N,N-dimethyltryptamine. Five known compounds
were also isolated. Although the new natural products did not show strong bioactivity, three of
the isolated bis-indole alkaloids, borreverine, 4-methylborreverine and
dimethylisoborreverine, showed potent activity with IC50 values between 190 – 670 nM against
Chapter 4 reports the isolation of three new isoborreverine-type alkaloids, 10,10’-
dimethoxydimethylisoborreverine, 10-methoxydimethylisoborreverine and 10’-
methoxydimethylisoborreverine from the bark of F. pimenteliana. Two known borreverinetype alkaloids were also isolated. The moderate anti-plasmodial activity of these alkaloids is
reported, with IC50 values ranging from 959 – 2407 ng/mL. Further insights into structureactivity relationships of borreverine-type alkaloids are also discussed.
Chapter 5 reports the chemical investigation of the roots of A. pubescens, from which a highly
unusual oxidized furo[2,3-c]xanthene, acrotrione, was isolated along with two known
acetophenones. Acrotrione is the first natural product of its class to be isolated. Moderate
anti-plasmodial activity for the natural products is reported, with IC50 values ranging from 1.7
to 4.7 µM.
Chapter 6 reports the isolation of one new quinoline alkaloid, leptanoine D, from P.
haplophyllus. Nine known alkaloids were also isolated. The chemotaxonomic relationships
between the monotypic Pitaviaster genus and the related Australian genera Euodia, Melicope
and Acronychia are discussed.
The secondary goal of this thesis was to investigate the factors that influence diversity of
natural products in Australian plants. In recent years, natural product-driven drug discovery
has seen a decrease in popularity in the pharmaceutical industry, part of which has been
caused by the repeated isolation of known natural products. In response to this, there is a
requirement for the development of new ideas that expedite the discovery of new natural
products. Some recent publications have noted that natural product diversity is positively
correlated with diversity of plant-herbivore communities. This may suggest that plants in
regions of high biotic stress (i.e. rainforests) should be the focal point of terrestrial plant
natural product drug discovery. We aimed to validate this hypothesis by using the Australian
Rutaceae genus Flindersia as a case study. Contrary to expectations, our results showed that
Flindersia species growing in arid regions of central Australia produced a significantly higher
number of structurally unique alkaloids than rainforest species. These unexpected results
highlight the potential of the Australian arid zone as a source of new natural products.||