New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold

 

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dc.contributor.advisor Chibale, Kelly en_ZA
dc.contributor.author Ntuli, Nelson Axe en_ZA
dc.date.accessioned 2014-08-13T14:28:54Z
dc.date.available 2014-08-13T14:28:54Z
dc.date.issued 2005 en_ZA
dc.identifier.citation Ntuli, N. 2005. New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/6352
dc.description Includes bibliographical references (leaves 120-125). en_ZA
dc.description.abstract Many antimalarial drugs including chloroquine are no longer effective against the disease, as their efficacy has been decreased by the spread of drug resistant strains. This loss has been a major barrier to the effective treatment of malaria and has necessitated an urgent need to discover new antimalarial drugs. New 4-aminoquinoline isatin derivatives have been designed and synthesised. Isatin was used as a biologically validated starting point for the design of chemical libraries directed at the intended target due to its privileged nature. Included in the design of these isatin derivatives is the thiosemicarbazone moiety previously demonstrated to inhibit cysteine proteases from mUltiple protozoan parasites. Synthesized compounds were tested against the enzyme falcipain-2 (Rec-FP-2) as well as the parasite source of this protease, Plasmodium Jalciparum (P.f. W2). The results of structure activity relationship studies demonstrate the influence of substituents at position 5 of the isatin scaffold. With respect to the chain length, a two carbon methylene spacer between the aminoquinoline and isatin moieties, was found optimum. A 5-bromo isatin derivative with this spacer, compound 79b, was found to be the most active with an IC₅₀ value of 163.5 nM against the W2 parasite strain and second most active against the enzyme (lC₅₀ = 3.65 μM). en_ZA
dc.language.iso eng en_ZA
dc.subject.other Chemistry en_ZA
dc.title New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold en_ZA
dc.type Master 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 Masters
dc.type.qualificationname MSc en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Ntuli, N. A. (2005). <i>New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/6352 en_ZA
dc.identifier.chicagocitation Ntuli, Nelson Axe. <i>"New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2005. http://hdl.handle.net/11427/6352 en_ZA
dc.identifier.vancouvercitation Ntuli NA. New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2005 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/6352 en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Ntuli, Nelson Axe AB - Many antimalarial drugs including chloroquine are no longer effective against the disease, as their efficacy has been decreased by the spread of drug resistant strains. This loss has been a major barrier to the effective treatment of malaria and has necessitated an urgent need to discover new antimalarial drugs. New 4-aminoquinoline isatin derivatives have been designed and synthesised. Isatin was used as a biologically validated starting point for the design of chemical libraries directed at the intended target due to its privileged nature. Included in the design of these isatin derivatives is the thiosemicarbazone moiety previously demonstrated to inhibit cysteine proteases from mUltiple protozoan parasites. Synthesized compounds were tested against the enzyme falcipain-2 (Rec-FP-2) as well as the parasite source of this protease, Plasmodium Jalciparum (P.f. W2). The results of structure activity relationship studies demonstrate the influence of substituents at position 5 of the isatin scaffold. With respect to the chain length, a two carbon methylene spacer between the aminoquinoline and isatin moieties, was found optimum. A 5-bromo isatin derivative with this spacer, compound 79b, was found to be the most active with an IC₅₀ value of 163.5 nM against the W2 parasite strain and second most active against the enzyme (lC₅₀ = 3.65 μM). DA - 2005 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2005 T1 - New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold TI - New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold UR - http://hdl.handle.net/11427/6352 ER - en_ZA


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