Design and study of bioorganometallic artemisinins as antimicrobials
| dc.contributor.advisor | Chellan, Prinessa | en_ZA |
| dc.contributor.advisor | Strauss, Erick | en_ZA |
| dc.contributor.author | Albertyn, Christoff Christiaan | en_ZA |
| dc.contributor.other | Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. | en_ZA |
| dc.date.accessioned | 2021-06-11T10:18:50Z | |
| dc.date.accessioned | 2021-12-22T14:11:10Z | |
| dc.date.available | 2021-06-11T10:18:50Z | |
| dc.date.available | 2021-12-22T14:11:10Z | |
| dc.date.issued | 2021-12 | |
| dc.description | Thesis (MSc)--Stellenbosch University, 2021. | en_ZA |
| dc.description.abstract | ENGLISH ABSTRACT: Due to the rise in artemisinin resistant Plasmodium falciparum strains, the main focus of this study was to maintain and increase the efficacy of artemisinin to optimise the production of reactive oxygen species (ROS) released from artemisinin. To achieve this, the moieties, ruthenium p-cymene and ferrocene, known to increase electrochemical reactions, were used to derivatise the artemisinin structure for new possible drug candidates. Artemisinin was modified into a triazole (compounds 1-3) and artesunate (compounds 4-6) derivatives. Generally greater yields for the artesunate derivatives (45-63%) were obtained compared to the triazole derivatives (8-42%). Two new artemisinin ligands, compounds 1 and 4, that can coordinate with a variety of organometallic moieties were successfully synthesised and characterised. Although optimisation to the synthesis of compound 1 is required (21% yield), likely due to the interaction of the copper (I) catalyst with the endoperoxide bridge, high purity could be achieved using easily accessible gravity column chromatography (98% pure). Moreover, two major stereo isomers of compound 1 could be isolated for future studies. Two new ferrocenyl compounds 3 and 6 were obtained and fully characterised. The synthesis and characterisation of a new ferrocene precursor, intermediate 3, was also obtained in high yield (86%) and purity (> 99%). Ruthenium complexes, compounds 2 and 5, were much more challenging to obtain and purify (“± 40%” purity) compared to the ferrocenyl derivatives, compounds 3 (98% pure) and 6 (99% pure). Solubility studies revealed that the triazole derivatives were generally less soluble (10-80 µM) in the biological buffer system (PBS and HEPES) compared to the artesunate derivatives (10-160 µM). In vitro biological studies showed the influence of the halogen ligand on ruthenium complexes 2 and 5 did indicate that the bulkier and more polar iodido-derivative (2b: 69.8 ± 0.58 nM Dd2) had a slightly higher activity against P. falciparum than its chlorido-counterparts (2a: 70.9 ± 2.6 nM Dd2). Furthermore, data suggested that the ferrocenyl derivatives were the most active against the P. falciparum parasite, with compound 6 with the highest activity of 3.0 ±0.49 nM against the chloroquine resistant strain (Dd2). Overall, the data indicated that the isolated organometallic groups do not have any significant activity but requires the artemisinin moiety to improve activity. The unexpected, but most satisfactory result, was the very low toxicity of the compounds synthesised. The artemisinin derivatives tested against Escherichia coli and Staphylococcus aureus strains, unfortunately did not yield any promising biological data to prove that artemisinin could be effective as an antibacterial drug, due to solubility complications with most of the compounds (1-3 and 6). Furthermore, only compound 4 proved capable of decreasing bacterial growth of the E. coli and S. aureus at the maximal tested concentration, 500 µM, to 53.0 ± 2.3 % active growth and 70.8 ± 2.8 % active growth, respectively. However, compound 4 had much greater growth inhibition against the E. coli compared to the base artemisinin drug (93 ± 1.8 % active growth) and even the proposed active dihydroartemisinin species (77.7 ± 3.4% active growth). The findings in this project are preliminary and further studies, directing towards artesunate derivatives and similar artesunate species, is needed. Therefore, these results could shift our understanding of which derivatisation is more likely to improve upon the pharmacological properties artemisinin lacks. Data further suggested that the ferrocenyl species can be developed further along with similar sandwich type organometallic complexes. | |
| dc.description.abstract | AFRIKAANSE OPSOMMING: Hierdie projek fokus op die verbetering van artemisinin om weerstandige stamme van Plasmodium falciparum te bestry. Die hoofdoel was om die vervaardiging van reaktiewe suurstof spesies (ROS) wat deur artemisinin geproduseer is, te vermeerder . Artemisinin kan verbeter word deur ruthenium p-cymene en ferrocene, wat elektrochemiese reaksies verbeter, aan die artemisinin struktuur te bind. Die organo-metaal verbindings was met verskeie triasool verbindings (verbindings 1-3) óf deur artesunate verbindings (verbindings 4-6) verbind met artemisinin. Die algehele opbrengs van die artesunate verbindings het tussen 45-63% gelê, hoër as die van die triasool verbindings wat tussen 8-42% gelê het. Die twee nuwe verbindings 1 en 4, wat met verskeie organo-metaal verbindings kan bind, was albei suksesvol gesintetiseer en gekarakteriseer. Alhoewel die maksimale opbrengs vir verbinding 1 (21%) laag was, weens die redoks reaksie tussen die koper (I) katalis met die endo-peroksied brug, was ’n hoë graad van suiwerheid bereik (98%). Benewens die feit dat ’n hoë suiwerheid verkry was, is twee stereo-isomere geïdentifiseer wat vir toekomstige studies geïsoleer kan word. Verder was twee nuwe ferroseen-verbindings (3 en 6) suksesvol gesintetiseer en gekarakteriseer. “Intermediate 3”, ’n nuwe ferroseen-voorloper verbinding, was met hoë opbrengs (86%) gesintetiseer en het ‘n hoë suiwerheid bereik (>99%). Ruthenium-kompleks verbindings 2 en 5 was, na verskeie pogings om die verbindings te genereer, suksesvol gesintetiseer, maar onsuksesvol om ‘n hoë graad van suiwerheid te bereik (± 40% suiwer), wat laag is in vergelyking met die ferroseen-verbindings 3 (98% suiwer) en 6 (99% suiwer). Die oplosbaarheid toetse het aangetoon dat die triasool-verbindings wel minder oplosbaar (10-80 µM) is in beide buffer sisteme (PBS en HEPES) as met die artesunate verbindings (10-160 µM). In vitro biologiese toetse teen die P. falciparum parasiet dui aan dat die ruthenium verbindings 2 en 5 meer aktiwiteit toon met die jodium-afstammeling (2b: 69.8 ± 0.58 nM Dd2) as met die chloried-afstammeling (2a: 70.9 ± 2.6 nM Dd2). Van die organo-metaal verbindings, toon ferroseen-verbindings hoofsaaklik die sterkste biologiese aktiwiteit teen P. falciparum. Verbinding 6 met ’n aktiwiteit van 3.0 ± 0.49 nM teen die chloroquine weerstandige stam (Dd2), is ‘n goeie voorbeeld hiervan. Verdere afleidings meen dat die organo-metaal verbindings op hulle eie min na geen aktiwiteit teen die malaria parasiet toon, maar toon wel verhoogde aktiwiteit nadat dit met die artemisinin verbinding geheg is. Die verbindings gesintetiseer tydens die projek toon baie lae toksisiteit teen gesonde menslike selle. Weens swak oplosbaarheid in die biologiese buffer vir bakteriële toetse, het die meeste verbindings min na geen biologiese aktiwiteit teen Escherichia coli en Staphylococcus aureus stamme getoon. Van al die verbindings kon slegs verbindings 4 en 5a getoets word, maar slegs 4 teen die hoogste getoetste konsentrasie (500 µM), toon die beste groei inhibisie teen E. coli (53.0 ± 2.3 % ooflewend) en S. aureus (70.8 ± 2.8 % oorlewend). Verbinding 4 het wel hoër aktiwiteit as artemisinin (93 ± 1.8 % oorlewend) en dihydroartemisinin teen E. coli (77.7 ± 3.4% oorlewend) getoon. Hierdie projek is slegs ’n voorlopige studie om verskeie nuwe idees en verdere ondersoeke vir toekomstige projekte te skep. Die data van hierdie projek dui ondermeer aan dat artesunate-verbindings en onder meer, ferroseen-verbindings, die beste keuses sou wees om verdere ondersoeke te loods ten einde aan artemisinin verbeterde farmaseutiese eienskappe te gee. | |
| dc.description.version | Masters | en_ZA |
| dc.format.extent | 117 pages : illustrations | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/10019.1/123591 | |
| dc.language.iso | en_ZA | en_ZA |
| dc.publisher | Stellenbosch : Stellenbosch University | en_ZA |
| dc.rights.holder | Stellenbosch University | en_ZA |
| dc.subject | UCTD | en_ZA |
| dc.subject | Antimicrobial drugs | en_ZA |
| dc.subject | Bioorganic chemistry | en_ZA |
| dc.subject | Artemisinin | en_ZA |
| dc.title | Design and study of bioorganometallic artemisinins as antimicrobials | en_ZA |
| dc.type | Thesis | en_ZA |