Doctoral Degrees (Chemistry and Polymer Science)
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Browsing Doctoral Degrees (Chemistry and Polymer Science) by browse.metadata.advisor "Blackie, Margaret A. L."
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- ItemDesign 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.
- ItemThe development of N-functionalized 4-azapodophyllotoxins as novel anticancer agents(Stellenbosch : Stellenbosch University, 2020, 2020-12) Botes, Marthinus Gerhardus; Van Otterlo, Willem Arjen Lodewyk; Blackie, Margaret A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: As malignant carcinomas are one of the world’s leading causes of death in terms of non- communicable diseases, there is a strong need for the development of highly specific antiproliferative agents. Cancer is also an ever-increasing concern in Africa, so the there is also a need to develop anticancer agents that are easily accessible through short synthetic strategies. To this end, we have synthesized a small library of more than 30 novel N-functionalized 4- azapodophyllotoxin analogues and analysed these compounds for their antiproliferative activity. The compounds were synthesized in overall yields of 35-57% for the 4N-aryl derivatives and 18-35% for the 4N-triazolo derivatives. Multicomponent reactions (MCRs) were employed as the main method for the synthesis of the desired scaffolds, after optimizing the procedure to afford the desired compounds from N-functionalized naphthylamines. The N- propargyl analogues were further derivatised through “click” chemistry with a range of different azides. The antiproliferative activity of these compounds were determined against an oesophageal cancer cell line, WHCO1. Two of the 4N-triazolo analogues exhibited inhibitory activities comparable to the known anticancer agent cisplatin (IC50 = 9.2 μM). These were 11-(4-hydroxy-3,5-dimethoxyphenyl)-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,11- dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (231, IC50 = 8.8 μM) and 4-((1- ((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3- triazol-4-yl)methyl)-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin- 1(3H)-one (232, IC50 = 8.3 μM). The 4N-aryl analogues also showed good inhibitory activity, with IC50 values ranging between 11-35 μM, with 4-(4-fluorobenzyl)-11-(4-hydroxy-3,5- dimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (181, IC50 = 11.7 μM) and 4-benzyl-11-(3,4,5-trimethoxyphenyl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (185, IC50 = 12.9 μM) the most potent of these compounds. The 4N-propargyl 4- azapodophyllotoxin analogues were also evaluated for their antiproliferative activity, however, the analogues containing the podophyllotoxin and etoposide-derived pendent rings, 174 and 176, respectively) were found to be inactive. The analogues with the modified E-rings were, interestingly, fairly potent inhibitors, as 11-(3,5-dibromo-4-hydroxyphenyl)-4-(prop-2-yn-1-yl)- 4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (177, IC50 = 2.7 μM) and 11-(5-bromo-2- hydroxyphenyl)-4-(prop-2-yn-1-yl)-4,11-dihydrobenzo[g]furo[3,4-b]quinolin-1(3H)-one (178, IC50 = 23.3 μM) were active against the WHCO1 cell line. We have also undertaken in silico molecular modelling studies through the use of the Schrödinger Maestro suite, so as to supplement our biological evaluation data and in so doing gain more understanding into the potential active sites that these molecules target. These molecular modelling studies did confirm literature observations that noted the importance of the 4′-hydroxyl group on the pendent E-ring of this class of compounds. This was observed in the favourable docking scores of active compounds such as 177, 181 and 231 against the active site of topoisomerase II. As these compounds strongly mimic etoposide, the molecular modelling studies on the topoisomerase II crystal structure (PDB ID: 3QX3) also gave insight as to why the 4N-triazolo- glycoside 4-azapodophyllotoxins fared better in the antiproliferative studies than the 4N-aryl analogues, as π-π interactions between the triazole ring and the adenosine group on the DNA fragment could be observed. The glycoside groups were stabilized in the solvent exposed region of the active pocket. New insights have thus been gained into the structure-activity relationships of these compounds through the combination of biological evaluation and in silico molecular modelling.
- ItemInvestigating the formation of multicomponent crystals of antiplasmodial agents(Stellenbosch : Stellenbosch University, 2019-03) Clements, Monica Jade; Blackie, Margaret A. L.; Le Roex, Tanya; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: The aim of this project was to explore the formation of multicomponent crystals of some known, as well as some novel, antiplasmodial agents and investigate and compare structures and properties of the antiplasmodials and the multicomponent crystals that they form. A series of five known 4-aminoquinoline antiplasmodial agents were chosen and the formation of multicomponent crystals with these compounds was investigated. The use of molecular electrostatic potential surfaces (MEPS) to calculate molecular complementarity with a specific coformer allowed us to rank a list of coformers according to the probability of forming multicomponent crystals with each 4- aminoquinoline. A total of nineteen multicomponent forms were obtained by liquid-assisted grinding, and these were characterised by PXRD, IR, TGA and DSC. Possible reasons are given for why two of the five 4-aminoquinolines yielded only amorphous multicomponent products, while three yielded crystalline products. Additionally, a brief discussion is given for the reasonably low success rate (38%) of the MEPS method for coformer selection. Attempts were then made to synthesise a series of novel aminoferrocene-containing lapatinib analogues so that the abovementioned knowledge could be applied to a novel system. While, we successfully achieved the synthesis of the precursor fragments, the key reaction that coupled the aminoferrocene fragment to the lapatinib core – the Suzuki-Miyaura reaction – proved more challenging than expected. After substantial effort, the desired product was obtained (as detected by LC-MS), however it could not be isolated, most likely due to low yields. The use of an amine or amide linker (instead of a direct carbon-carbon bond) was also investigated, however these attempts were also unsuccessful. A series of 6-substituted quinazolin-4(3H)-ones, formed serendipitously during the synthesis of the lapatinib analogues, were also studied for their ability to form multicomponent crystals. The MEPS method to select coformers was applied and liquid-assisted grinding was used to form eight novel multicomponent crystals. Interestingly, only one of the quinazolinone derivatives formed multicomponent crystals with the chosen coformers, while the remaining three yielded only mixtures of starting materials. Possible explanations for this were explored and it is clear that there are additional factors that play a larger role than initially thought. This study shows that quinoline- and quinazolinone-based antiplasmodial agents warrant further attention for the formation of multicomponent crystals. The work described in this thesis provides a greater understanding of the ability of these molecules to form multicomponent crystals. Together with similar studies, this knowledge could be applied to related systems, which would one day allow for accurate predictions and the formation of multicomponent crystals of antiplasmodial agents with tailored properties.
- ItemSynthesis of fused heterocyclic aromatic compounds as potential antiplasmodial agents(Stellenbosch : Stellenbosch University, 2017-12) Jacobs, Leon; Blackie, Margaret A. L.; Pelly, S. C.ENGLISH ABSTRACT: 3-Methyl benzofuran antiplasmodial compounds have been described in literature and and synthesis of heterocyclic derivatives forms the basis of this project. These benzofuran compounds were synthesized with the primary role as effective inhibitors of the enzyme Plasmodium falciparum N-Myristoyl transferase (PfNMT). PfNMT plays an important enzymatic function in the majority of all living organisms, facilitating the myristoylation of N-terminal glycine residues of proteins that serve many functions in vivo, and is considered vital to the viability of not only most organisms, but P. falciparum too. The rationale behind the key features of these antiplasmodial compounds include the heterocyclic scaffold that induces π – π stacking with amino acid residues at the active site of PfNMT, aromatic amide and ester groups also necessary for π – π stacking and a piperidinium salt coupled to the heterocycle, providing a salt-bridge interaction with neighboring amino acid residues. Five different heterocycles were synthesized with the primary function of replacing the benzofuran moiety in order to ascertain which heterocyclic system is the most efficacious. We synthesized indole, 3-methyl indole, 1-methyl benzimidazole, benzoxazole and benzothiophene scaffolds, each containing an ester group at the C2-position necessary for transesterification and amidation reactions, as well as a phenolic group at the C4-position (C7-position for the benzimidazole scaffold) required for the introduction of a piperidine group. The Boc-protected piperidine group was introduced first, followed by esterification reactions with 2-phenylethanol, benzyl alcohol and 1-naphthalenemethanol. Amidation reactions were also carried out with 2-phenethylamine, benzylamine, 1-naphthylmethylamine and 4-(aminomethyl)pyridine. The synthesis of each series of heterocyclic antiplasmodials was realized after the final Boc-deprotection step, providing all the compounds in salt form. These compounds were sent for whole-cell testing against a P. falciparum chloroquine sensitive strain (NF54) with the intention to prove which heterocycle and aromatic ester or amide substituent improves the efficacy the most, and validate the importance of a methyl group on the 3-methyl indole and 1-methyl benzimidazole scaffold when comparing the efficacy of analogous esters and amides. The results indicated that the benzoxazole series of compounds were inactive and the 3-methyl indole series are the most active which returned IC50 values of 0.56 – 6.1 μM respectively, but is trailed closely in efficacy by the indole (IC50 values of 0.83 – 6.5 μM) and benzothiophene (IC50 values of 0.71 – 5.9 μM) series of compounds. The 1-methyl benzimidazole series of compounds were the least active with IC50 values between 7.4 – 13.3 μM apart from one compound indicating an IC50 value of 1.1 μM.