Design, synthesis and pharmaceutical application of novel polycyclic 'cage' diamines.
Onajole, Oluseye Kehinde.
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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).