Malaria remains one of the greatest problems facing developing nations, especially in sub-Saharan Africa. Part of the problem stems from increased resistance to current treatments hence there is a large drive to develop novel antimalarial compounds. Several chelating compounds, including 8-hydroxyquinoline (8-HQ), 1,10- phenanthroline (1,10-phen) and 2,2.6,2-terpyridine (terpy), have disputed activities (8-HQ and 1,10-phen) or are untested (terpy). Furthermore the mechanism(s) by which these ligands and/or their complexes with metal ions exhibit their toxic effect is unknown. In order to resolve these issues, a study of the antimalarial activities of the free ligands, the ligands complexed with metal ions (Au 3+, Cu 2+, Fe 3+, Pd 2+ and Pt 2+), and the ligands with free metals in solution were measured. The ligands, complexes and metals were also tested for their ability to inhibit β-haematin formation, the mode of action ascribed to the most widely used antimalarial, chloroquine. The background toxicity levels of the various metal ions (previously unreported) were also measured and are reported here. None of the ligands were found to have particularly high activity (all approximately 1μM). In general the metals in were found to have no beneficial effect on activity whether complexed or freely available in solution. None of the ligands were found to inhibit β-haematin formation. The complexes however, with the exception of those of Cu 2+, all inhibited β-haematin formation. Upon further investigation it was found that the each of the metal ions with the exception of Cu 2+ had an innate ability to inhibit β-haematin formation. Thus the mode of action of the ligands and the complexes is likely to be via different mechanisms. In an attempt to enhance the activities of the ligands they were modified by covalently linking them to nutrients essential to the malaria parasite (adenosine and pantothenic acid). These six novel compounds however, showed no improvement in action. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2008.

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / History / Master / Master of Philosophy

No description available.

Thesis (M.Sc.)(Bioinformatics))-University of Pretoria, 2007. / Summary in English. Includes bibliographical references. Available on the Internet via the World Wide Web.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Malaria is one of the most deadly parasitic diseases known to man. Although the number of malaria cases reported each year is decreasing, this disease continues to pose health and economic problems mainly in developing countries. Significant progress has been made in the fight against this disease. This includes the discovery and development of potent antimalarial agents. However, the development of resistance to most of these potent antimalarials has made the development of new antiplasmodial agents of paramount importance. Several promising antiplasmodial agents have been found from the marine environment. Amongst these are the tetraprenylated toluquinols from the brown alga: Sargassum heterophyllum. These metabolites have been reported to exhibit a range of antiplasmodial activity; however, the mechanisms by which these compounds bring about their antiplasmodial activity and the pharmacophoric groups responsible for such activity are unknown. Two species of Sargassum algae were encountered during the course of this project. From the investigation of the geographical and seasonal variation of metabolites of S. heterophyllum and S. elegans we established that there were no significant intra and inter site variations amongst metabolite profiles of both species both within and between the sampled seasons. These results enabled us to establish that the collection of both species from three different sites on the eastern coast of South Africa namely; Kenton on Sea, Port Alfred and Noordhoek in autumn, winter or spring would qualitatively yield the same metabolites. A comparison of metabolite profiles of both species also revealed no qualitative differences between metabolites of S. heterophyllum and S. elegans. The quantities of selected prenylated metabolites extracted from S. heterophyllum using four different extraction techniques was also assessed using qNMR as the method of quantification. This led to the identification of optimal extraction techniques and conditions for the extraction of sargahydroquinoic acid (1.38), sargaquinoic aid (1.39) and sargachromenol (2.10) from S. heterophyllum. From this study, the extraction of algae by soxhlet extraction using EtOH as the extraction solvent led to the extraction of the highest quantities of sargahydroquinoic acid. The potential of other extraction techniques such as microwave assisted extraction, to yield high quantities of the selected metabolites were also identified. With gram quantities of sargahydroquinoic acid (1.38) in hand, this compound was modified by oxidation, reduction, acetylation, methylation and cyclization reactions to yield nine derivatives. The derivatives and four naturally occurring prenylated toluquinols were assessed for antiplasmodial and cytotoxic activity against the FCR-3 Gambian Chloroquine resistant strain of P. falciparum and the MDA-MB-231 breast carcinoma cell line respectively. Comparison of antiplasmodial data for all twelve compounds showed that the hydroquinone moeity of sargahydroquinoic acid (1.38) is important for antiplasmodial activity while esterification of the carboxylic acid group in 1.38 resulted in more potent antiplasmodial compounds. Of all twelve compounds, compound 5.2, the hydroquinone methyl ester of 1.38 was found to be the most potent antiplasmodial compound with an IC₅₀ value of 1.94 μM and a selectivity index of 22.68.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Master of Science June, 30, 2015 / The world suffers under a serious threat of malaria with about 584 000 deaths reported each year and most of these fatalities being children under five years of age. Malaria is caused by the protozoan parasite of the genus Plasmodium. Five different malaria species infect humans and cause disease: P. vivax, P. malariae, P. ovale, P. knowlesi and the cause of most malaria deaths, P. falciparum. The main reason for this disturbing situation is the emergence of drug resistance which reduces the effectiveness of most antimalarials. Hence, there is an urgent need for new drugs that will possibly be effective against both wild type and mutant strains of Plasmodium species. Pyrimethamine, a dihydrofolate reductase (DHFR) inhibitor, has been used most widely as an antimalarial antifolate drug for the treatment of malaria. However, rapid development of parasite resistance to this drug occurred because of its rigidity. Parasitic resistance to antimalarial antifolates arises from single mutations at various amino acid residues surrounding the PfDHFR active site. In this project, we aimed to design and synthesise a novel series of flexible pyrimidine analogues of a dihydrotriazine hit compound prepared in a previous study. These compounds were designed to target folate metabolism in the malaria parasite. The initial series of compounds prepared in this project were synthesised over 5 steps in an overall yield of 10%. The flexible pyrimidine analogues were screened for antimalarial activity in an in vitro P. falciparum screen on the Gambian FCR-3 strain (chloroquine and cycloguanil resistant strain) with dihydroartemisinin, methotrexate and quinine as controls. 5-(3-(3,5-Dichlorophenoxy)propyl)-6-phenylpyrimidine-2,4-diamine displayed the best antimalarial activity (IC50 = 0.09 μM) of the compounds in this series. Surprisingly; this was the only compound prepared in this series that proved to be as effective as our original hit dihydrotriazine (IC50 ~50 nM). In the second generation of compounds prepared in this study, we used a multicomponent coupling approach to synthesise three flexible pyrimidines bearing a non-aromatic side chain at the 6-position of the pyrimidine ring. For comparison, two analogues bearing a phenyl group at the 6-position of the pyrimidine ring were also prepared. Once again; only one compound of this series [5-((4-chlorophenethylamino)methyl)-6-cyclopropylpyrimidine-2,4-diamine, (IC50 = 0.03 μM)] showed activity comparable with our original hit compound. iv Finally, ten substituted pyrimidines bearing a flexible side chain at the 6-position of the pyrimidine ring, were prepared. These compounds are structurally similar to P65, [6-methyl-5-(3-(2,4,5-trichlorophenoxy)propoxy)pyrimidine-2,4-diamine] an analogue of a potent antifolate, WR99210, found to have good oral bioavailability in rats. Once again, the antimalarial activity of the compounds prepared was assessed in an in vitro P. falciparum screen on the Gambian FCR-3 strain. The most promising compound of this series was 6-(3-(3,4-dichlorophenoxy)propoxy)pyrimidine-2,4-diamine, which exhibited antimalarial activity in the low micromolar range (IC50 = 4.46 μM).

Pang, Lap-yin. / "42" in title is subscript. / "July 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 163-173). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.