Synthesis and biological evaluation of pyrimidine and isoquinoline inhibitors as potential antimalarial antifolates and transmission-blocking agents

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dc.contributor.authorSomandi, Khonzisizwe
dc.date.accessioned2024-01-25T10:16:56Z
dc.date.available2024-01-25T10:16:56Z
dc.date.issued2024
dc.descriptionA thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Science, School of Chemistry, University of the Witwatersrand, Johannesburg, 2023
dc.description.abstractMalaria continues to be a serious threat, in particular to the African region. According to the World Health Organisation, in 2021, 247 million malaria cases were reported globally of which 95 % and 96 % of malaria related deaths were in the African region. The persistence of the disease, amongst it being difficult to treat and kill, is also attributed to its resistance to currently used antimalarial agents, including class II antifolate drugs such as pyrimethamine, which are used to target the P. falciparum dihydrofolate reductase (PfDHFR) enzyme. However many other drugs have lost activity because of mutations in the active site of the enzyme. The first component of the research described herein has been to synthesise 2,4- diaminopyrimidine analogues that work by disrupting folate metabolism by inhibiting PfDHFR. In a four step synthetic approach we have successfully prepared a series of pyrimidine-2,4-diamines possessing a flexible four atom linker at the 5-position of the pyrimidine ring (in yields of 33-96 %), which could prove advantageous in avoiding clashes with mutant amino acids in the enzyme active site. Enzyme inhibition assays of the compounds have shown successful inhibition of the wild-type (WT) and quadruple mutant (QM) PfDHFR in nM ranges (Ki-WT; 1.27 – 242.72 nM and Ki-QM; 13.01 – 208.23 nM). A moderate antiplasmodial activity in vitro was observed for all compounds assessed against the drug sensitive strain IC50 (TM4/8.2) 0.42 – 28.0 µM and the drug resistant strain IC50(V1S) 3.72 – 53.7 µM. The second component of the research focuses on the synthesis of transmission-blocking analogues that target the sexual stage of the malaria parasite life cycle and work by inhibiting stage IV/V gametocytes which prevents the transmission of the parasite from the human host back to the feeding mosquito. A series of 3-substituted-isoquinolin-1-yl benzamides, derivatives of the hit compound MMV1581558, have been successfully prepared in a synthetic protocol that involves only two steps from relatively simple precursors, in yields ranging between 14 – 68 %. All analogues are undergoing biological assessment against stage IV/V gametocytes and currently we have only received the results of the asexual blood stage activity assay, with most analogues displaying only moderate activity (IC50 1.18 – 7 µM). Additional biological assays are still underway
dc.description.librarianTL (2024)
dc.description.sponsorshipNational Research Foundation (NRF) Postgraduate Merit Award
dc.facultyFaculty of Science
dc.identifier.urihttps://hdl.handle.net/10539/37415
dc.language.isoen
dc.phd.titlePhD
dc.schoolChemistry
dc.subjectMalaria
dc.subjectDiaminopyrimidine
dc.titleSynthesis and biological evaluation of pyrimidine and isoquinoline inhibitors as potential antimalarial antifolates and transmission-blocking agents
dc.typeThesis
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