Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics

 

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dc.contributor.advisor Egan, Timothy J en_ZA
dc.contributor.advisor Hunter, Roger en_ZA
dc.contributor.author Woodland, John Geoffrey en_ZA
dc.date.accessioned 2017-01-23T07:54:31Z
dc.date.available 2017-01-23T07:54:31Z
dc.date.issued 2016 en_ZA
dc.identifier.citation Woodland, J. 2016. Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/22912
dc.description.abstract For centuries, quinoline-based drugs have formed the cornerstone of antimalarial treatment. Despite recent challenges posed by resistance, interest in these molecules persists. It is thus surprising that crucial details of their mechanism of action against the most virulent malaria parasite, Plasmodium falciparum, remain unresolved. This thesis develops new tools to generate deeper insights into the modes of action of the two major classes of the quinoline antimalarials against P. falciparum. These are the quinoline methanols, represented by the diastereomeric Cinchona alkaloids quinine and quinidine, and the 4-aminoquinolines, represented by chloroquine. Mechanistic studies of these antimalarials have typically focused on the inhibition of haemozoin biocrystallisation within the acidic digestive vacuole of P. falciparum. In order to conduct a comprehensive survey of the subcellular localisation of these antimalarials across the entire infected erythrocyte, a suite of novel fluorescent derivatives was designed and synthesised. Key physicochemical properties of these antimalarials were retained in order to preserve the interactions of these drugs with their putative target, ferriprotoporphyrin IX or Fe(III)PPIX. Versatile derivatisation of the alkaloids was enabled by a regioselective radical-mediated thiolene click reduction. 7-Nitrobenz-2-oxa-1,3-diazole (NBD) was identified as a suitable reporter fluorophore and was attached to the quinoline core by nucleophilic aromatic substitution. The length of the spacer chain between the quinoline and the fluorophore was varied by preparing NBD-labelled amino acids and their corresponding succinimidyl esters. A novel NBD-labelled chloroquine derivative was prepared by using its N-dealkylated analogue as a key intermediate. A single quinine derivative with an alternative fluorophore, bimane, was also prepared. en_ZA
dc.language.iso eng en_ZA
dc.subject.other Chemistry en_ZA
dc.title Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics en_ZA
dc.type Doctoral Thesis
uct.type.publication Research en_ZA
uct.type.resource Thesis en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Science en_ZA
dc.publisher.department Department of Chemistry en_ZA
dc.type.qualificationlevel Doctoral
dc.type.qualificationname PhD en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Woodland, J. G. (2016). <i>Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/22912 en_ZA
dc.identifier.chicagocitation Woodland, John Geoffrey. <i>"Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2016. http://hdl.handle.net/11427/22912 en_ZA
dc.identifier.vancouvercitation Woodland JG. Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2016 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/22912 en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Woodland, John Geoffrey AB - For centuries, quinoline-based drugs have formed the cornerstone of antimalarial treatment. Despite recent challenges posed by resistance, interest in these molecules persists. It is thus surprising that crucial details of their mechanism of action against the most virulent malaria parasite, Plasmodium falciparum, remain unresolved. This thesis develops new tools to generate deeper insights into the modes of action of the two major classes of the quinoline antimalarials against P. falciparum. These are the quinoline methanols, represented by the diastereomeric Cinchona alkaloids quinine and quinidine, and the 4-aminoquinolines, represented by chloroquine. Mechanistic studies of these antimalarials have typically focused on the inhibition of haemozoin biocrystallisation within the acidic digestive vacuole of P. falciparum. In order to conduct a comprehensive survey of the subcellular localisation of these antimalarials across the entire infected erythrocyte, a suite of novel fluorescent derivatives was designed and synthesised. Key physicochemical properties of these antimalarials were retained in order to preserve the interactions of these drugs with their putative target, ferriprotoporphyrin IX or Fe(III)PPIX. Versatile derivatisation of the alkaloids was enabled by a regioselective radical-mediated thiolene click reduction. 7-Nitrobenz-2-oxa-1,3-diazole (NBD) was identified as a suitable reporter fluorophore and was attached to the quinoline core by nucleophilic aromatic substitution. The length of the spacer chain between the quinoline and the fluorophore was varied by preparing NBD-labelled amino acids and their corresponding succinimidyl esters. A novel NBD-labelled chloroquine derivative was prepared by using its N-dealkylated analogue as a key intermediate. A single quinine derivative with an alternative fluorophore, bimane, was also prepared. DA - 2016 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics TI - Insights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics UR - http://hdl.handle.net/11427/22912 ER - en_ZA


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