Department of Chemistry and Polymer Science

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Browsing Department of Chemistry and Polymer Science by browse.metadata.advisor "Blackie, M. A. L."

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    Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors
    (2021-12) Nematswerani, Ronewa; Blackie, M. A. L.; van Otterlo, W. A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH SUMMARY: Glycogen synthase kinase 3 (GSK-3) has become a promising CNS target, since GSK-3 inhibitors have been shown to have full therapeutic potential in CNS disorders particularly in the multifactorial neuropathogenesis of Alzheimer’s disease (AD). This project focuses on the second-generation of new potential irreversible GSK-3β inhibitors, building on prior research on first-generation of compounds. Molecular modelling was carried out on the GSK-3β protein to design and identify a series of urea compounds containing suitable electrophilic warheads that have the important interactions with the binding site. The docking scores of proposed compounds were better than that of the reference GSK-3β inhibitor AR-A014418 (AstraZeneca). The library contained three sets of 1-aryl-3-(4-methoxybenzyl)ureas wherein the incorporated aryl group is the three benzazoles namely: benzothiazole, benzimidazole and benzoxazole. Incorporation of different electrophilic warheads were investigated in silico in four positions (4th, 5th, 6th and 7th) of the benzazole ring, with the potential to form an irreversible, covalent bond with nucleophilic Cys199 in the GSK-3β ATP binding pocket. Cys199 was targeted for this covalent modification as it was suggested as a new strategy for the development of novel, potent, selective GSK-3β inhibitors. Overall, the synthesis was possible on two variant positions (5th and 6th) to produce a library of novel irreversible GSK-3β and precursors with potential anti-Alzheimer’s disease activities. A total of three compounds and five precursors were successfully synthesised and were fully characterised using standard spectroscopic and analytical techniques.