Browsing by Author "Albertyn, Christoff Christiaan"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Design and study of bioorganometallic artemisinins as antimicrobials
    (Stellenbosch : Stellenbosch University, 2021-12) Albertyn, Christoff Christiaan; Chellan, Prinessa; Strauss, Erick; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    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.