Browsing by Author "Hay, Jonathan Bruce"

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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 and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer
    (Stellenbosch : Stellenbosch University, 2021, 2021-12) Hay, Jonathan Bruce; Blackie, Margaret; Willem, van Otterlo; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: In this study, the design and synthesis of a series of 12 known and novel 2,4-substituted benzofuran and benzothiophene derivatives, 4 known 4-aminoquinolines and 16 novel dual heterocyclic hybrids are described. The series of hybrid compounds was successfully synthesized by amide and ester functional group couplings of benzofuran carboxylic acid derivatives with 4-aminoquinolines, and similarly, benzothiophene carboxylic acids with 4- aminoquinolines. In addition, a short investigation into the synthesis of symmetrical heterocycles successfully produced two novel bis-benzothiophene compounds. These known and novel heterocycle and hybrid compounds were screened in vitro against the chloroquine sensitive NF54 strain of Plasmodium falciparum to evaluate their potential as antiplasmodial agents. The results from the biological screening are presented and discussed for the heterocycles and indicated that the benzofuran and benzothiophene analogues exhibited poor antiplasmodial activity (IC50: >10 μM). In contrast, the entire series of novel dual heterocyclic compounds exhibited good antiplasmodial activity with IC50 values between 0.089 μM and 2.75 μM concentrations, with the four known 4-aminoquinolines showing antiplasmodial activity between 0.090 μM and 5.84 μM concentrations. A small group of hybrids and the two symmetrical compounds were also subjected to preliminary in vitro anticancer screening against WHCO1 oesophageal cancer cells to evaluate whether there was any potential for these types of compounds to be cancer inhibitors. Results obtained from the preliminary screening indicated that there was indeed anticancer activity with IC50 values below 10 μM, however there are still some results outstanding to confirm the initial data. This study has provided results in support of dual heterocyclic hybrid compounds based on benzofuran/quinoline and benzothiophene/quinoline scaffolds, that have the potential to inhibit Plasmodium falciparum and can be viable scaffolds for designing new antimalarial drugs.