Single and hybrid antimalarials based on artemisinin, chloroquine and ß-lactams : synthesis, antiplasmodial activity, cytotoxicity and effect of selected artemisinin-chloroquine hybrids on the parasitic endocytosis pathway

Doctoral Thesis


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University of Cape Town

Malaria remains to be one of the leading causes of morbidity and mortality throughout recorded history. It is caused by protozoan parasites of the genus Plasmodium, where P. falciparum is the most lethal. Current estimates are that over 500 million people are afflicted, while 3 million people die annually. With the emergence of resistance to antimalarial drugs in the malaria parasite, it is critical to develop new chemotherapeutic agents that can combat the disease and/or overcome resistance. This may be achieved by identifying molecules that target or interfere with unique parasitic pathways such as haemoglobin degradation or parasitic endocytosis. This thesis describes the design and synthesis of novel antimalarial agents based on the ‘Designed Multiple Ligand’ approach. Compounds were synthesized via conjugate addition or multi-component condensation reaction. 4-Aminoquinolines were hybridized with artemisinin or 1,4-naphthoquinone derivatives; selected hybrids were further investigated for their effect on the parasitic endocytosis pathway and compared to the effect of chloroquine and artemisinin on the same pathway. The effects of drug treatment on the morphology and haemoglobin levels in the parasites as well as localization of transport vesicles via immunofluorescence microscopy were determined. A series of β-lactam derivatives containing a terminal acetylene moiety were synthesized via the Staudinger and Ugi 3-component 4-centre condensation reactions. The compound with the best activity from the series was used to couple these reactions to post-condensation chemical modifications via the Mannich reaction, another multi-component reaction, to create a more diversified library. A small series of 4-aminoquinoline analogues, including amodiaquine-like compounds and bisquinoline derivatives, was also prepared in an attempt to elucidate their structure-activity relationships. The antiplasmodial and cytotoxic activities were determined for all compounds; where applicable, assays on β-haematin inhibitory activity were also carried out.

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