Small molecules with anti-trypanosomal and anti-leishmanial activity

Gehrke, Sebastian (2012) Small molecules with anti-trypanosomal and anti-leishmanial activity. Doctoral thesis, University of East Anglia.

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Parasitic diseases such as Human African Trypanosomiasis (HAT), Chagas disease and Leishmaniasis
cause thousands of fatalities each year. Current chemotherapy is based on drugs
discovered over 60 years ago that are expensive and difficult to administer. The drug-pipeline
is virtually dry and the trickle of inhibitors that are in development are largely based on those
that are already in use. Parasite resistance to these drugs is developing, underlining the urgent
need for novel anti-parasitic drug therapies.
This study focused on the identification of novel small molecular inhibitors with anti-parasitic
activities against Trypanosoma brucei spp. (HAT), Trypanosoma cruzi spp. (Chagas disease)
and Leishmania infantum spp. (Leishmaniasis) with a particular focus on combining broadspectrum
activity with parasite-specificity.
A two-pronged approach was used to develop an effective chemotherapy through the optimisation
of known inhibitors of glycophosphatidylinositol (GPI)-anchor biosynthesis and improving
the specificity of iron chelators.
GPI anchor biosynthesis is a pathway essential for survival to all three parasites. Here, a
rhodanine-N-acetic acid derivative served as the starting point for the development of a library
of 379 thiazolidine-4-one and pyrazolone analogues. These were systematically screened
against three species of parasitic protozoa and a mammalian cell line in order to identify inhibitors
which demonstrate low-�M anti-parasitic activity and a good selectivity profile.
Further target identification studies on the effect of these new inhibitors using in vitro assays
confirmed inhibition of GPI anchor biosynthesis as a mode of action. This provides further
evidence that the GPI anchor is a druggable target for the development of novel anti-parasitic
agents against T. brucei, T. cruzi and L. infantum. Taken together, this work indicates that
drugs targeting one feature common to all three protozoa can provide anti-parasitic activity
with low toxicity against mammalian cells.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Zoe White
Date Deposited: 29 Nov 2013 16:09
Last Modified: 29 Jan 2014 11:29


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