Masters Degrees (Chemistry and Polymer Science)

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Browsing Masters Degrees (Chemistry and Polymer Science) by browse.metadata.advisor "Chellan, Prinessa"

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    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.
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    Development of new antimalarial ferrocenyl-artesunate complexes
    (Stellenbosch : Stellenbosch University, 2023-03) Munnik, Brandon Liam; Chellan, Prinessa; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Despite declining numbers over the past 20 years, malaria, which is caused by the parasite Plasmodium falciparum, remains a serious issue in many parts of the world, especially in Africa. This problem is further exacerbated by the arrival of the COVID-19 pandemic, which led to difficulties in service delivery to third-world countries. The World Health Organization shifted to the use of artemisinin-based combination therapy in order to counteract increasing resistance to chloroquine. However, as of 2004, resistance to artemisinin-based combination therapy has been on the rise. Organometallic drugs have shown promise in combatting malaria strains that are resistant to chloroquine, a previously used quinoline based drug. Ferroquine is a ferrocene containing chloroquine hybrid, which has made it to phase II clinical trials and is a prime example of improving activity through metal conjugation. Artesunate (Ars), a derivative of artemisinin, is a semisynthetic antimalarial drug and forms part of the artemisinin-based combination therapy arsenal. The drug functions mainly by activation of its endoperoxide bridge leading to increased oxidative stress in malaria parasites. The goal of this project was to prepare four ferrocenyl containing artesunate derivatives to explore the effects of combining the two moieties. The complexes were all obtained in moderate yields with high purity and characterized by 1H and 13C{ 1H} NMR spectroscopy as well as electrospray ionisation mass spectrometry and the redox profiles were examined using cyclic voltammetry. All the complexes demonstrated good activity against the model Apicomplexa Toxoplasma gondii (T. gondii) with IC50 values in the low micromolar range (0.28-1.2 µM). T. gondii was further used to investigate a potential mode of action (MoA). It was determined that the mode of action for the MoA of the organometallic conjugates was through the generation of reactive oxygen species, the same as that of the parent drug, artesunate. However, in the case of the artesunate-ferrocenyl ethyl amide (C3) a novel mechanism of death to the parasite was observed using immunofluorescence microscopy. All complexes showed good to excellent antimalarial Stellenbosch University https://scholar.sun.ac.za iii activity against the chloroquine sensitive strain of Plasmodium falciparum (P. falciparum, NF54), with IC50 values ranging from 12 to 4858 nM. The complexes all showed low cytotoxicity towards the two healthy cell lines tested – Human embryonic kidney (HEK293) and Human prostatic cells (PNT1A) – and high selectivity for T. gondii over healthy cells. Future work will involve testing the complexes as potential anticancer agents and further looking into the novel mechanism of action demonstrated by the artesunate-ferrocenyl ethyl amide (C3). This could potentially be done by attaching a fluorescent probe to the drug and monitoring where the drug accumulates.
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    The synthesis and evaluation of new organometallic benzimidazole Complexes as antiplasmodials
    (Stellenbosch : Stellenbosch University, 2020, 2020-12) Jordaan, Lydia; Chellan, Prinessa; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Despite ongoing efforts to discover new antimalarial drugs, malaria remains a serious concern in developing countries due to the widespread resistance of Plasmodium falciparum (P. falciparum) to antimalarial drugs such as chloroquine. Organometallic complexes, particularly those containing platinum group metals have shown great promise for the development of new antimalarial treatments. The majority of antiplasmodial organometallic complexes reported in the literature are derived from quinoline-containing ligands. Benzimidazole is an attractive pharmacophore as it has displayed various pharmacological activities and can bind to a range of biological receptors. Few organometallic complexes of benzimidazoles have been reported, and even fewer that display antimalarial activity. In this study, two known and four new cationic iridium and rhodium complexes were synthesised from 2-(2-pyridyl)benzimidazole and metal dimers with different η5-Cpx groups (x = Me, ph or biph). Six new neutral cyclometallated iridium and rhodium complexes of 2- phenylbenzimidazole were also synthesised, as several C^N cyclometallated complexes reported in the literature have displayed improved biological activities compared to their N^N analogues. All complexes were obtained in moderate to good yields with high purity. The complexes were characterised using infrared and 1H and 13C NMR spectroscopy as well as mass spectrometry. The single crystal X-ray structures of the pyridyl complexes were obtained and confirmed the expected molecular structures. The pyridyl (C1 – C6) and phenyl complexes (C7 – C12) all displayed moderate to good antiplasmodial activity against the CQ-sensitive 3D7 strain of P. falciparum. The pyridyl complexes were also evaluated against the CQ-resistant Dd2 strain and, in general, improved activities were observed compared to 3D7. In general, the rhodium complexes out-performed the iridium complexes in both series and an increase in activity was observed when the cyclopentadienyl group was extended, in the order Cp* < Cpxph < Cpxbiph. This can be attributed to increased hydrophobicity. The cyclometallated rhodium Cpxbiph complex, which is the most active of the cyclometallated complexes, deviates from this trend. The pyridyl complexes exhibited low cytotoxicity to human embryonic kidney (HEK) cells compared to their activity against P. falciparum strains, which is an indication of good selectivity. Future work will involve investigating potential mechanism of action of these complexes, performing further in vitro biological tests on the cyclometallated complexes and potentially modifying the ligand to improve the antimalarial activities of these complexes. Overall, the newly synthesised pyridyl and cyclometallated organometallic complexes are promising candidates for further investigation as potential antimalarial agents.
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    Synthesis and study of sulfonamide containing organometallic complexes as inhibitors for infectious disease
    (Stellenbosch : Stellenbosch University, 2019-12) Kotze, Timothy J.; Chellan, Prinessa; Smith, Gregory S.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Six imino sulfadoxine derivatised iridium complexes (C1 - C6), previously synthesized in literature, were investigated for drug like character by accessing their aqueous solubility through a turbidimetric assay and probing the potential active species by means of aquation experiments. The complexes C3, C5 and C6 had solubilities ranging between 20 μM and 160 μM, while C1, C2 and C4 had solubilities greater than 160 μM. Solubility was found to decrease with increasing addition of hydrophobic groups to the half-sandwich moiety coordinating via a centroidal bond to the iridium metal centre. Ease of hydrolysis of the chlorido ligand was found to decrease as the steric bulk around the metal centre was increased to the point that the chlorido of C3 remained in-tact under mild conditions in the presence of silver nitrate. This likely means the active species is the, as synthesized, chlorido complex. New synthetic methods were developed for the synthesis of the Schiff base ligands of these complexes to achieve a more efficient synthesis and obtain pure samples for testing. Though pure samples were not obtained, the efficiency of the synthesis was improved. Six new amido sulfadoxine derivatised iridium complexes (C7 – C12), were synthesized in moderate to good yields of 56% – 84% as yellow powders. Their ligands were synthesized through in situ generation of an acid chloride and subsequent quenching with sulfadoxine. A crystal structure was obtained for the pyridyl amido sulfadoxine ligand which crystallised in the triclinic, P1, space group as transparent needle like crystals. The drug-like character was also investigated for this series of complexes and their solubilities of C9, C11 and C12 were between 20 μM and 60 μM, while C7, C8 and C10 were greater than 160 μM. The same results were obtained for the aquation experiments as for C1 – C6. All complexes were tested against Mycobacterium tuberculosis (Mtb) strain H37Rv and Plasmodium falciparum strains, 3D7, Dd2 and HB3. Complex C6 was only tested against Mtb. The imino complexes were more active in general, with a MIC90 of 2.78 μM for C6 against strain H37Rv after 7 days and an IC50 of 13.8 μM for C5 against strain 3D7. Although the amido complexes exhibited promising activity against P. falciparum with C12 having an IC50 of 0.975 μM against strain 3D7 and IC50 of 0.766 μM against multidrug resistant strain Dd2. The activity was generally seen to increase as the solubility decreased with the addition of hydrophobic groups to the complexes.