Browsing by Author "Hamann, Anton Ruben"

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    Design and development of novel irreversible GSK-3β inhibitors to address Alzheimer's disease
    (Stellenbosch : Stellenbosch University, 2018-03) Hamann, Anton Ruben; Blackie, Margaret A. L.; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Molecular modelling on the GSK-3β protein was carried out to identify a library of suitable electrophilic warhead containing ligands that have the necessary interactions with the binding site. Several series of novel irreversible inhibitors for GSK-3β with potential anti-Alzheimer‟s disease activities were then synthesised. In total, eleven compounds were successfully synthesised. The compounds have been fully characterised using standard spectroscopic and analytical techniques. The scaffold, 5-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}pyrazin-2-amine, was equipped with an α,β-enone Michael acceptor, that allowed for the coupling of various side chains using substitution chemistry. A library of two different series with an internal Michael acceptor was synthesised. The synthesis of the third series that consisted of a terminal Michael acceptor or a halomethylketone was attempted but proved futile. Suzuki-Miyaura chemistry has been thoroughly explored to find the best conditions to offer the products in acceptable yields. Pd(dppf)Cl2 as a catalyst, in a solvent system of toluene:ethanol:water, was found to be the best candidate for the Suzuki-Miyaura reactions to synthesise the aforementioned scaffold. The compounds were tested against the human recombinant GSK-3β and were found to have weak to good activity (GSK-3β IC50 range: 0.12 - >10 μM). The most active compound (GSK-3β IC50: 0.12 μM) consisted of a pyridine ring and the carbonyl of the Michael acceptor is situated directly next to the aminopyrazine core. The results showed that the libraries have the potential to be expanded into a second generation of new compounds.