Masters Degrees (Chemistry and Polymer Science)

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Browsing Masters Degrees (Chemistry and Polymer Science) by Subject "Alzheimer’s disease -- Therapeutics"

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    Design, synthesis and biological activity studies of 1-aryl-3-(4-methoxybenzyl)ureas as proposed irreversible GSK-3 inhibitors in Alzheimer’s disease therapeutic development
    (Stellenbosch : Stellenbosch University, 2019-03) Venter, Jana; Blackie, Margaret A. L.; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterised by memory loss and cognitive decline. No cure has been found for the disease yet, therefore the development of disease-modifying therapeutics (DMTs), which can target the underlying mechanisms of AD, is necessary. Glycogen synthase kinase 3 (GSK-3) has become a promising CNS target, since GSK-3 dysregulation has been shown to play a central role in the multifactorial neuropathogenesis of AD. In this project, a proposed library of structurally-related, irreversible GSK-3β inhibitors was modelled, synthesised, characterised and biologically tested as potential AD drug candidates. The library contained two sets of 1-aryl-3-(4-methoxybenzyl)ureas wherein the incorporated aryl group was a benzothiazole or benzimidazole scaffold, respectively. Different electrophilic warheads were incorporated onto the scaffolds, with the potential to form a covalent, irreversible bond with nucleophilic Cys199 in the GSK-3 ATP pocket. Targeting of Cys199 was suggested to provide increased GSK-3 selectivity, since Cys199 is exchanged with other amino acids in structurally-related enzymes. A library of 10 covalent inhibitors containing the nitrile, halomethylketone (HMK), vinyl ketone, ethynyl ketone and acrylamide electrophilic warheads was successfully synthesised, as well as the reference GSK-3 inhibitor, AR-A014418 (AstraZeneca). The synthetic route commenced with the preparation of the 6-substituted 2-aminobenzothiazoles and 6-substituted 2-aminobenzimidazoles in good yields. Thereafter, the scaffolds were coupled to 4-methoxybenzylamine through carbonyldiimidazole-mediated urea formation, which afforded excellent yields for the benzothiazoles and moderate yields for the benzimidazoles, proposedly due to tautomeric effects in the latter. These ureas were further modified in position 6 of the benzazole scaffolds, to incorporate the respective electrophilic warheads. The GSK-3β inhibitory activity results were promising, with high activities measured for the nitrilesubstituted ureas and the HMK-substituted benzimidazole urea. In comparison to the reference GSK-3 inhibitor, which displayed an IC50 value of 0.072 ± 0.043 μM in the assay, the best IC50 value obtained in the library was 0.086 ± 0.023 μM, observed for 1-(6-cyano-1H-benzo[d]imidazol-2-yl)-3-(4- methoxybenzyl)urea. In general, the benzimidazole series displayed better IC50 values than the equivalent inhibitors in the benzothiazole series. Although an initial assay was carried out to ascertain whether the newly synthesised inhibitors were in fact irreversible inhibitors, the results remain ambiguous and further study is required to confirm this hypothesis. In conclusion, highly active GSK-3β inhibitors were successfully developed and may potentially contribute to future AD drug development.