Repositioning of astemizole for malaria

dc.contributor.advisorChibale, Kelly
dc.contributor.authorMambwe, Dickson
dc.date.accessioned2022-02-25T09:27:39Z
dc.date.available2022-02-25T09:27:39Z
dc.date.issued2021
dc.date.updated2022-02-25T09:27:15Z
dc.description.abstractMalaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date.
dc.identifier.apacitationMambwe, D. (2021). <i>Repositioning of astemizole for malaria</i>. (). ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/35849en_ZA
dc.identifier.chicagocitationMambwe, Dickson. <i>"Repositioning of astemizole for malaria."</i> ., ,Faculty of Science ,Department of Chemistry, 2021. http://hdl.handle.net/11427/35849en_ZA
dc.identifier.citationMambwe, D. 2021. Repositioning of astemizole for malaria. . ,Faculty of Science ,Department of Chemistry. http://hdl.handle.net/11427/35849en_ZA
dc.identifier.ris TY - Doctoral Thesis AU - Mambwe, Dickson AB - Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date. DA - 2021 DB - OpenUCT DP - University of Cape Town KW - chemistry LK - https://open.uct.ac.za PY - 2021 T1 - Repositioning of astemizole for malaria TI - Repositioning of astemizole for malaria UR - http://hdl.handle.net/11427/35849 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35849
dc.identifier.vancouvercitationMambwe D. Repositioning of astemizole for malaria. []. ,Faculty of Science ,Department of Chemistry, 2021 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/35849en_ZA
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Chemistry
dc.publisher.facultyFaculty of Science
dc.subjectchemistry
dc.titleRepositioning of astemizole for malaria
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationlevelPhD
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