Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues

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dc.contributor.advisorChibale, Kellyen_ZA
dc.contributor.advisorMasimirembwa, Collenen_ZA
dc.contributor.authorOngarora, Dennis Sure Bagwasien_ZA
dc.date.accessioned2014-11-07T09:20:31Z
dc.date.available2014-11-07T09:20:31Z
dc.date.issued2014en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractMalaria is a major cause of morbidity and mortality globally, resulting in over 200 million cases and 650, 000 deaths in 2010 according to the 2012 WHO Malaria Report. Furthermore, malaria endemicity is associated with poor economic growth. One of the greatest challenges facing malaria chemotherapy is the emergence of Plasmodium strains resistant to all known clinically used antimalarials. This underscores the need for the development of new drugs that retain efficacy against the resistant parasites. In this study, analogue-based drug design was employed as a form of drug ‘rescue’ in the development of novel potential antimalarials. The main aim was to design and synthesize analogues of the 4-aminoquinoline drug amodiaquine with potentially improved safety and efficacy profiles using prior knowledge of the drug metabolism and pharmacokinetics (DMPK), toxicity and efficacy profile of the drug. A representative set of compounds in four different series was synthesized in which the 4-aminoquinoline ring was coupled with benzothiazole, benzimidazole, benzoxazole and pyridyl rings bearing different aliphatic amines and diamines. The chemistry involved aromatic nucleophilic substitution reactions and hydrogenation of nitro aromatic compounds. Benzothiazole and benzoxazole analogues with a tertiary protonatable nitrogen were found to possess potent antiplasmodial activity against the drug resistant W2 and K1 Plasmodium falciparum strains.en_ZA
dc.identifier.apacitationOngarora, D. S. B. (2014). <i>Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/9309en_ZA
dc.identifier.chicagocitationOngarora, Dennis Sure Bagwasi. <i>"Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2014. http://hdl.handle.net/11427/9309en_ZA
dc.identifier.citationOngarora, D. 2014. Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Ongarora, Dennis Sure Bagwasi AB - Malaria is a major cause of morbidity and mortality globally, resulting in over 200 million cases and 650, 000 deaths in 2010 according to the 2012 WHO Malaria Report. Furthermore, malaria endemicity is associated with poor economic growth. One of the greatest challenges facing malaria chemotherapy is the emergence of Plasmodium strains resistant to all known clinically used antimalarials. This underscores the need for the development of new drugs that retain efficacy against the resistant parasites. In this study, analogue-based drug design was employed as a form of drug ‘rescue’ in the development of novel potential antimalarials. The main aim was to design and synthesize analogues of the 4-aminoquinoline drug amodiaquine with potentially improved safety and efficacy profiles using prior knowledge of the drug metabolism and pharmacokinetics (DMPK), toxicity and efficacy profile of the drug. A representative set of compounds in four different series was synthesized in which the 4-aminoquinoline ring was coupled with benzothiazole, benzimidazole, benzoxazole and pyridyl rings bearing different aliphatic amines and diamines. The chemistry involved aromatic nucleophilic substitution reactions and hydrogenation of nitro aromatic compounds. Benzothiazole and benzoxazole analogues with a tertiary protonatable nitrogen were found to possess potent antiplasmodial activity against the drug resistant W2 and K1 Plasmodium falciparum strains. DA - 2014 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues TI - Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues UR - http://hdl.handle.net/11427/9309 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/9309
dc.identifier.vancouvercitationOngarora DSB. Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2014 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/9309en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.titleAntimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analoguesen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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