Malaria endemic areas not only pose a public health threat, but affects 3.3 billion people worldwide. In 2011, estimated malaria related deaths amounted to 660 000 out of 219 million reported cases, with 81% of these and 91% of malaria related mortality occurred in the African region. Those most affected were pregnant women, children under the age of five and immunocompromised individuals. Malaria is the fifth deadliest disease worldwide and accounts for the second highest death rate in Africa, following HIV/Aids. To combat this parasitic infection of antiquity, the ideal malaria pharmacotherapy would be a cost effective and easily obtainable monotherapy. The malaria parasite, however, has an intrinsic ability to develop drug resistance through various mechanisms. Widespread resistance towards antimalarial drugs has rendered traditionally used drugs therapeutically ineffective, hence accentuating the efficacy of the artemisinins as first line treatment option for uncomplicated Plasmodium falciparum (P. falciparum). A devastating reality of the challenging battle against malaria is the confirmed prolonged parasitic clearance times of the artemisinins, despite adequate drug exposure, which emphasises the urgent need for identifying and developing new, effective and safe therapies. During this study, 9-aminoacridines and artemisinin-acridine hybrids were successfully synthesised through nucleophillic substitution and their chemical structures confirmed by means of nuclear magnetic resonance spectroscopy (NMR), high resolution mass spectroscopy (HRMS) and infrared spectroscopy (IR). The hybrid compounds were synthesised through microwave assisted radiation, by covalently linking the artemisinin- and amino-functionalised acridine pharmacophores by means of a liable aminoethyl ether chain. The target compounds were screened in vitro for antimalarial activity against both the chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of P. falciparum. Their cytotoxicities were assessed against various mammalian cells of different origins, viz. the Chinese hamster ovarian cells (CHO) from animal origin, and from human origin, hepatocellular- (HepG2), neuroblastoma- (SH-SY5Y) and cervical cancer (HeLa) cells. The synthesised hybrids exhibited antimalarial activity against both Plasmodium strains. Compound 7, featuring an ethylenediamine moiety in the linker, was the most active hybrid, with 50% inhibitory concentration (IC50) values of 2.6 nM and 35.3 nM against the NF54 and Dd2 strains, respectively. It had gametocytocidal activity against the NF54 strain, comparable to dihydroartemisinin (DHA) and artesunate (AS) and it is significantly more potent than chloroquine (CQ), whilst possessing a resistance index value of 14, indicative of a significant loss of activity against the CQ resistant strain. Contrary, the promising hybrid 10, containing a 2-methylpiperazine linker, had gametocytocidal activity, comparable to CQ and was found to be six-fold more potent than CQ against the Dd2 strain, with a resistance index (RI) value of 2, whilst it further showed highly selective action towards the parasitic cells. Compound 10 was also found to possess anticancer activity against the HeLa cell line, comparable to DHA and AS, but fivefold higher than that of CQ, with the same levels of hepatotoxicity and neurotoxicity. The artemisinin-acridine hybrids displayed superior antimalarial activity, compared to the derived 9-aminoacridines against both the Plasmodium strains. They, however, did not have the ability to overcome resistance, reduce the toxicity of acridine, nor induce synergistic activity. The hybrids, indeed displayed promising anticancer activity against HeLa cells. It is anticipated that these compounds may stand as drug candidates for further investigation in the search for new anti-cervical cancer drugs, rather than as antimalarials. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Malaria endemic areas not only pose a public health threat, but affects 3.3 billion people worldwide. In 2011, estimated malaria related deaths amounted to 660 000 out of 219 million reported cases, with 81% of these and 91% of malaria related mortality occurred in the African region. Those most affected were pregnant women, children under the age of five and immunocompromised individuals. Malaria is the fifth deadliest disease worldwide and accounts for the second highest death rate in Africa, following HIV/Aids. To combat this parasitic infection of antiquity, the ideal malaria pharmacotherapy would be a cost effective and easily obtainable monotherapy. The malaria parasite, however, has an intrinsic ability to develop drug resistance through various mechanisms. Widespread resistance towards antimalarial drugs has rendered traditionally used drugs therapeutically ineffective, hence accentuating the efficacy of the artemisinins as first line treatment option for uncomplicated Plasmodium falciparum (P. falciparum). A devastating reality of the challenging battle against malaria is the confirmed prolonged parasitic clearance times of the artemisinins, despite adequate drug exposure, which emphasises the urgent need for identifying and developing new, effective and safe therapies. During this study, 9-aminoacridines and artemisinin-acridine hybrids were successfully synthesised through nucleophillic substitution and their chemical structures confirmed by means of nuclear magnetic resonance spectroscopy (NMR), high resolution mass spectroscopy (HRMS) and infrared spectroscopy (IR). The hybrid compounds were synthesised through microwave assisted radiation, by covalently linking the artemisinin- and amino-functionalised acridine pharmacophores by means of a liable aminoethyl ether chain. The target compounds were screened in vitro for antimalarial activity against both the chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of P. falciparum. Their cytotoxicities were assessed against various mammalian cells of different origins, viz. the Chinese hamster ovarian cells (CHO) from animal origin, and from human origin, hepatocellular- (HepG2), neuroblastoma- (SH-SY5Y) and cervical cancer (HeLa) cells. The synthesised hybrids exhibited antimalarial activity against both Plasmodium strains. Compound 7, featuring an ethylenediamine moiety in the linker, was the most active hybrid, with 50% inhibitory concentration (IC50) values of 2.6 nM and 35.3 nM against the NF54 and Dd2 strains, respectively. It had gametocytocidal activity against the NF54 strain, comparable to dihydroartemisinin (DHA) and artesunate (AS) and it is significantly more potent than chloroquine (CQ), whilst possessing a resistance index value of 14, indicative of a significant loss of activity against the CQ resistant strain. Contrary, the promising hybrid 10, containing a 2-methylpiperazine linker, had gametocytocidal activity, comparable to CQ and was found to be six-fold more potent than CQ against the Dd2 strain, with a resistance index (RI) value of 2, whilst it further showed highly selective action towards the parasitic cells. Compound 10 was also found to possess anticancer activity against the HeLa cell line, comparable to DHA and AS, but fivefold higher than that of CQ, with the same levels of hepatotoxicity and neurotoxicity. The artemisinin-acridine hybrids displayed superior antimalarial activity, compared to the derived 9-aminoacridines against both the Plasmodium strains. They, however, did not have the ability to overcome resistance, reduce the toxicity of acridine, nor induce synergistic activity. The hybrids, indeed displayed promising anticancer activity against HeLa cells. It is anticipated that these compounds may stand as drug candidates for further investigation in the search for new anti-cervical cancer drugs, rather than as antimalarials. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

The perpetual conflict in Darfur, Sudan, which started anew in 2003, had dire humanitarian consequences and threatened international peace and security. The UN Security Council, which has the primary responsibility for maintaining international peace and security, adopted Resolution 1769 on 31 July 2007 and authorised a 26 000 person-strong joint African Union/United Nations hybrid operation in Darfur (UNAMID) to take over from AMIS (the African Union peace operation in Darfur). UNAMID was established with dual command and control linked to both the African Union and the United Nations and both organisations would have an equal say in its mandate and operations. Given this unique and unprecedented arrangement between a regional organisation and the United Nations in terms of maintaining international peace and security, the aim of this research was to: • Understand and describe the political motivations/reasons why the United Nations formed a hybrid peace operation with the African Union; • Establish in which way the aforementioned impacted on future efforts of the United Nations to maintain international peace and security, especially on the African continent; and, based on this, • To determine whether or not hybrid operations were a viable alternative for the United Nations to maintain international peace and security. By means of a thorough analysis of the theoretical underpinnings of international peace and security, an assessment of the peace and security architecture of the United Nations and the African Union, an investigation into the origins of the Darfur conflict, an examination of the structure and mandate of UNAMID, and through an empirical investigation, a new theoretical proposition is provided in the conclusion of the thesis. It is concluded that the UNAMID model, in practical terms, is not an optimal mechanism for the United Nations to use to maintain international peace and security because it suffers from numerous internal political inequities and operational inadequacies. / Thesis (Ph.D. (Political Studies))--North-West University, Potchefstroom Campus, 2012

The perpetual conflict in Darfur, Sudan, which started anew in 2003, had dire humanitarian consequences and threatened international peace and security. The UN Security Council, which has the primary responsibility for maintaining international peace and security, adopted Resolution 1769 on 31 July 2007 and authorised a 26 000 person-strong joint African Union/United Nations hybrid operation in Darfur (UNAMID) to take over from AMIS (the African Union peace operation in Darfur). UNAMID was established with dual command and control linked to both the African Union and the United Nations and both organisations would have an equal say in its mandate and operations. Given this unique and unprecedented arrangement between a regional organisation and the United Nations in terms of maintaining international peace and security, the aim of this research was to: • Understand and describe the political motivations/reasons why the United Nations formed a hybrid peace operation with the African Union; • Establish in which way the aforementioned impacted on future efforts of the United Nations to maintain international peace and security, especially on the African continent; and, based on this, • To determine whether or not hybrid operations were a viable alternative for the United Nations to maintain international peace and security. By means of a thorough analysis of the theoretical underpinnings of international peace and security, an assessment of the peace and security architecture of the United Nations and the African Union, an investigation into the origins of the Darfur conflict, an examination of the structure and mandate of UNAMID, and through an empirical investigation, a new theoretical proposition is provided in the conclusion of the thesis. It is concluded that the UNAMID model, in practical terms, is not an optimal mechanism for the United Nations to use to maintain international peace and security because it suffers from numerous internal political inequities and operational inadequacies. / Thesis (Ph.D. (Political Studies))--North-West University, Potchefstroom Campus, 2012