Despite over 50 centuries of living with the disease, tuberculosis (TB) still remains one of the
oldest and deadliest diseases known to man and is gradually becoming a serious threat to the
human race. According to the 2009 Global tuberculosis control report of the World Health
Organisation (WHO), it is estimated that about 9.4 million incident cases of TB occurred
globally. Of these cases an estimated 1.4 million were HIV positive of which 78 % were in the
African region while 13 % are located in the South-East Asia Region. An estimate of 1.3
million deaths was reportedly caused by TB among HIV negative people. South Africa has the
highest percentage of HIV patients living with tuberculosis. The design, synthesis and
evaluation of novel polycyclic ‘cage’ amines for their pharmaceutical profiles are presented in
this thesis. In this project a total of 12 novel intermediates and 31 novel products were
synthesised. A thorough NMR elucidation of the various structures was also pursued.
This study was motivated by the reported discovery of SQ109 by Sequella. SQ109 (N-Geranyl-
N’-(2-adamantyl)ethane-1,2-diamine) shares the same 1,2 ethylenediamine pharmacophore with
ethambutol (EMB), a commercial TB-drug. SQ109 also possess remarkable activity against
MDR-TB which includes the EMB resistant strain suggesting that SQ109 is a new anti-TB drug
and not an EMB analogue. SQ109 comprises of a polycyclic adamantane moiety, an isoprenyl
moiety and a diamine.
This study had three main aims, namely (a) the design and synthesis of novel polycyclic ‘cage’
amines derivatives; the polycyclic ‘cage’ moieties investigated in this study includes
adamantane, trishomocubane, oxa-pentacycloundecane, aza-pentacycloundecane,
pentacyclodecane and pentacycloundecane, (b) structural elucidation (using 2D NMR
techniques) of synthesized novel polycyclic ‘cage’ amine derivatives (c) the anti-mycobacterial
screening of novel polycyclic ‘cage’ amines derivatives against H37Rv, MDR (multi-drug
resistant) and XDR (extensively-drug resistant) strains of Mycobacteria tuberculosis and (d) the
anti-bacterial and anti-fungal screening of selected novel polycyclic ‘cage’ amine derivatives.
Furthermore, the design, synthesis and NMR elucidation of a family of similar novel PCU
diamine ligands are also reported herein. The aim of these ligands is to complex and transport
copper ions to the sites of inflammation caused by arthritus. The known pharmaceutical
properties of polycyclic ‘cage’ compounds such as their ability to cross membranes due to
improved drug lipophilicity makes them suitable candidates for such a study. This project stems
from a logic collaboration between UKZN, UCT (University of Cape Town) and CPUT (Cape
Peninsula University of Technology) to test some of these cage diamines for activity against
arthritus. Experimental work in this aspect is performed by the group of Prof. Graham E.
Jackson (UCT) and Dr. Sebusi Odisitse (UPUT). / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2010.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/5342 |
| Date | January 2010 |
| Creators | Onajole, Oluseye Kehinde. |
| Contributors | Govender, Patrick., Kruger, Hendrik Gert., Maguire, Glen Eamonn Mitchel., Govender, Thavendran. |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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