Masters Degrees (Chemistry and Polymer Science)

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Browsing Masters Degrees (Chemistry and Polymer Science) by browse.metadata.advisor "Blackie, Margaret A. L."

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    Design and synthesis of dual-active heterocyclic yybrid inhibitors for β-Hematin and plasmodium falciparum N-Myristoyltransferase
    (Stellenbosch : Stellenbosch University, 2016-03) Hay, Jonathan Bruce; Blackie, Margaret A. L.; De Villiers, Katherine A.; Stellenbosch University. Faculty of Engineering. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: The current project focused on the design and synthesis of a novel antiplasmodial dual-active conjugate hybrid compound based on an indole scaffold and known antiplasmodial quinolines. The two scaffolds were chosen to target independent pathways in the malaria parasite, namely N-myristoylation and hemozoin formation. Initially, a novel indole compound, ethyl 4-(piperidin-4-yloxy)-1H-indole-2-carboxylate, which would possibly function as a Plasmodium N-myristoylation inhibitor, was synthesised. This would also function as the precursor to the proposed hybrid compound. The synthetic methodology that was employed included the synthesis of starting materials, 2-(benzyloxy)benzaldehyde and ethyl 2-azidoacetate, utilizing well-known benzyl protection and substitution reactions. These compounds were condensed into an azide cinnamate, (Z)-ethyl 2-azido-3-[2-(benzyloxy)phenyl]acrylate, via the Knoevenagel condensation reaction. An alternative method was investigated to obtain the same azide compound via an Arbuzov ylide formation and Horner-Wadsworth-Emmons Wittig-type reaction to obtain an E-stereospecific cinnamate, (E)-ethyl 3-[2-(benzyloxy)phenyl]acrylate, followed by a cerium ammonium nitrate mediated azide addition to afford the azide cinnamate. The azide cinnamate was later subjected to a Hemmetsberger thermal cyclization to form the indole scaffold, ethyl 4-(benzyloxy)-1H-indole-2-carboxylate, followed by a Mitsunobu reaction to afford the novel indole compound. Saponification yielded the carboxylic acid indole derivative, 4-(benzyloxy)-1H-indole-2-carboxylic acid, which was to function as a precursor to the hybrid compound, since an amidation reaction was considered as a possible method for coupling the indole and quinoline scaffolds. Later, 4,7-disubstituted quinoline derivatives were targeted as these would function as the second heterocyclic scaffold for the intended hybrid compound. These were synthesized according to the Gould-Jacobs, Skraup and Doebner-Miller methods, using simple m-substituted anilines as starting materials. The Gould-Jacobs reaction provided the desired 4-chloro-7-substituted quinolines (7-Br, -F, -NO2, -CH3and -OCH3), however, the Skraup and Doebner-Miller reactions only provided the 7-substituted quinolines (7-Br, -CH3 and -OCH3) and required the use of a subsequent oxidation reaction to yield quinoline N-oxides that were later chlorinated to give the desired 4-chloro-7-substituted quinolines. Following the synthesis of the desired quinoline substructures, the 4-chloro-7-substituted quinolines were converted to the desired quinoline pendant groups, N1-7-X-quinolin-4-yl)ethane-1,2-diamine (X = CF3 and Cl), via a chloride substitution reaction using diamino ethane. Preliminary investigations were carried out to obtain the proposed hybrid compound and to ascertain whether an amidation reaction was suitable for the coupling of the two heterocyclic scaffolds. Given time constraints towards the end of the project, only an N, N′-carbonyldiimidazole (CDI) facilitated amidation was investigated. Unfortunately, the approach was not successful. The challenge remains therefore, to utilize the methodologies optimized in this project to investigate heterocyclic hybrid compounds as novel resistance reversers in the treatment of malaria.
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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.
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    Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor
    (Stellenbosch : Stellenbosch University, 2017-12) Brigg, Siobhan Ernan; Pelly, Stephen, C.; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: HIV-1 remains the worst pandemic faced by mankind since its discovery as the causative agent of AIDS in the early 1980s. An enormous amount of research has been done to find a cure, but to date there has been no success and resistance is widespread among the available treatment. This project focused on the development of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a rational design approach. The lead compound, ethyl 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole-2-carboxylate, was shown to have low nano-molar potency against HIV-1 (IC50 = 16 nM), however it had two main shortcomings which needed to be addressed; poor resistance profile and poor acid stability. Previous research had shown the resistance profile could be improved by introducing meta substitution on the phenyl moiety which interacts with Tyr181 of the NNRTI binding pocket (NNIBP). We were successful in synthesising several meta substituted phenyl derivatives of the lead compound and these were shown to be equally as potent as the lead compound. Their activity against resistant strains is yet to be determined as we are awaiting the results from biological testing. The presence of an acid labile methyl ether functionality on the molecule which was susceptible to an acid catalysed indole mediated SN1 substitution in aqueous acidic medium meant that the lead compound could never be considered as a candidate for an orally available drug. The methyl ether moiety was exchanged for a sulfide moiety and several of these derivatives were successfully synthesised. Acid stability tests showed that we were successful in our endeavour to improve the acid stability, offering an advantage over the lead compound despite a slight reduction in potency. However to completely eliminate the possibility of substitution, we replaced the methyl ether moiety for an ethyl group, successfully synthesising ethyl 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxylate and 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxamide and we are currently awaiting the results from biological testing to determine whether this derivative is active against HIV-1. The functionality in the 2-position of the indole was also investigated through the synthesis of 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole and 5-chloro-3-((methylthio)(phenyl)methyl)-1H-indole. These derivatives lacking a group in the 2-position of the indole showed significant reduction in potency. Replacement of the ethyl ester for an isobutyl ester to give isobutyl 5-chloro-3-((3,5-dimethylphenyl)(methylthio)methyl)-1H-indole-2-carboxylate, showed some maintenance of potency, however the larger side chain was not well accommodated in the NNIBP. The presence of a chiral centre on the lead compound, and all derivatives synthesised in the project, resulted in our final aim; we set out to develop a method for resolving these enantiomers. Unfortunately, although we employed a variety of different strategies, including the use of chiral auxiliaries and the classical resolution method of attempting to make diastereomeric salts, we were not successful in achieving this aim.
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    Synthesis and biological evaluation of novel ferroquine and phenylequine analogues
    (Stellenbosch : Stellenbosch University, 2013-03) Jacobs, Leon; Blackie, Margaret A. L.; De Villiers-Chen, Katherine; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    Please refer to full text to view abstract.
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    Synthesis of triazole-linked chloroquinoline derivatives as novel antimalarial agents
    (Stellenbosch : Stellenbosch University, 2013-03) Taleli, Lebusetsa; Van Otterlo, William A. L.; Blackie, Margaret A. L.; Pelly, Stephen; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    Aminoquinolines are important class of drugs that have been used for malaria chemotherapy for centuries. However, long-term exposure to these drugs leads to extensive spread of drug resistance. As such, modified chloroquinoline derivatives are being studied as alternative antimalarial agents with the possibility to overcome drug resistance associated with chloroquine analogues. In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazole ring to an ethyl and propyl carbon spacer with a distal amine motif were designed and synthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. The compounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyne precursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncoupling in the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). These compounds have been characterized by the combination of NMR, ESI+ HRMS and IR spectroscopic methods. The antiplasmodial activity of the compounds was investigated in vitro against P. falciparum strain NF54 using chloroquine as a reference drug together with a standard antimalarial drug artesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possess promising potency by way of the inhibition concentrations less than 250 nM with the lowest being 28 nM. The observed activities have been ascribed to the overall modifications such as the introduction of a triazole linker and changing of carbon chain length as these were the variables. The compounds are accordingly under further biological investigations and only the chloroquine sensitive results are reported in this work.
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    Towards the synthesis of makaluvamine-analogues
    (Stellenbosch : Stellenbosch University, 2015-04) Botes, Marthinus Gerhardus; Van Otterlo, Willem A. L.; Pelly, Stephen C.; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Cancer is one of the leading causes of death in developed countries and rising fast as a cause of death in developing countries. The increase of cancer prevalence in developing countries can be attributed to westernisation trends, with lifestyle cancers such as colorectal and lung cancer being amongst the most commonly reported malignant neoplasms. This means that the development of novel methods of treatment is essential in combatting this disease in the developing world. Combinational chemotherapy is one of the best candidates for treatment, but it is reliant on effective compounds targeting different modes of action. It also means that these compounds should be easily and cheaply available. Makaluvamines have been identified as a class of compounds that may have a novel mode of action on top of being known as topoisomerase II inhibitors. This study attempted to devise a short and concise synthetic strategy, based on reported procedures, to construct makaluvamine C analogues. This involved the introduction of a methyl group to an indole intermediate (7,8-dimethoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline), before oxidation to a quarternized pyrroloiminoquinone (7-methoxy-5-methyl-8-oxo-1,3,4,8- tetrahydropyrrolo[4,3,2-de]quinolin-5-ium chloride). The introduction of this methyl group proved problematic, as the indole substrate proved to be difficult to handle and tended to degrade under reaction conditions. The lack of initial success prompted the deviation from the initial route by quarternizing a quinoline intermediate to form a quinolinium iodide salt (4- (dimethoxymethyl)-6,7-dimethoxy-1-methyl-5-nitroquinolin-1-ium iodide). Upon reduction to give 4-(dimethoxymethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-amine, it was discovered that the subsequent ring-closing reaction to produce 7,8-dimethoxy-5-methyl- 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline was still problematic. The synthesis of the target compounds has not yet been successfully completed, but will still be pursued so these compounds can be evaluated for their anticancer activity and have their mode of action tested.