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Development of new metallo-drugs for haemozoin inhibition
Thesis (PhD)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2021
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| _version_ | 1867613776299163648 |
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| access_status_str | Open Access |
| author | Sammy, Chandre Jade |
| author2 | De Villiers, Katherine A. |
| author_browse | De Villiers, Katherine A. Sammy, Chandre Jade |
| author_facet | De Villiers, Katherine A. Sammy, Chandre Jade |
| author_sort | Sammy, Chandre Jade |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/110561 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:41:31.332Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/110561 Development of new metallo-drugs for haemozoin inhibition Sammy, Chandre Jade De Villiers, Katherine A. Chellan, Prinessa Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Antimalarials Metals in medicine Heterocyclic compounds UCTD Thesis (PhD)--Stellenbosch University, 2021. ENGLISH ABSTRACT: The work herein focuses on the synthesis and characterization of N,N′- and N,O′- coordinating acridine organometalic complexes of Ru(II), Rh(III), Ir(III) and ferrocene (Fc) for evaluation as new inhibitors of synthetic malaria pigment (β-haematin). Two new Schiff base ligands (L2 and L4) and four new Schiff base complexes (C4-C6, C8) were synthesised and characterized using multiple spectroscopic techniques including NMR spectroscopy, IR spectroscopy and mass spectrometry. The amide library, consisting of two ligands (AL1 and AL2) and seven complexes (AC1-AC7), are new and have not been previously reported. Electrochemical profiles of all ligands and complexes were investigated using cyclic voltammetry. The Ru(II), Rh(III) and Ir(III) complexes were able to access a range of oxidation states from +1 to +4, while the Fc complexes exhibited a reversible one electron electrochemical response corresponding to the Fc+/Fc redox couple. Furthermore, both libraries exhibited good to partial aqueous solubility, however, the amide compounds were found to be less soluble in comparison to the Schiff base compounds. All ligands and complexes showed good β-haematin inhibition activity in a detergent assay. Notably, the N,N′- Ru(II), Rh(III) and Ir(III) complexes for both libraries exhibited enhanced β-haematin inhibition activity over their respective ligand, with the exception of the quinolyl Rh(III) derivatives (C5 and AC5). In the case of AC5, this was related to the purity of the complex which could not be resolved. All compounds were found to adsorb onto preformed β-haematin, with log Kads values ranging from 3.7-6.5, consistent with both chloroquine and quinacrine (log Kads = 4.9 ± 0.3 and 4.5 ± 0.1, respectively). Spectrophotometric titrations in 40% (v/v) aqueous DMSO (pH 7.5) indicated that all compounds are able to associate with Fe(III)PPIX with the exception of the N,O′-coordinated Ru(II) complexes which was related to their poor stability. The in vitro biological activity of the Schiff base compounds was investigated against the CQ-sensitive 3D7 and CQ-resistant Dd2 parasite strains. The N,N′-coordinated complexes all exhibited low to sub micromolar activities with the Fc-containing compound, C9, exhibiting the most potent antiplasmodial activity. A significant correlation between in vitro antiplasmodial activity and association constants was found, which led to the proposal that the acridine metal complexes prepared in this work exert their toxicity by 1) inhibiting haemozoin formation via adsorption onto the crystal surface (as shown for β-haematin), and 2) forming association complexes with the resultant free Fe(III)PPIX which are responsible for parasite killing. AFRIKAANSE OPSOMMING: Hierdie werk fokus op die sintese en karakterisering van N,N′ en N,O′ -gekoördineerde akridien organometaalkomplekse van Ru(II), Rh(III) Ir(III) en ferroseen (Fc) as nuwe remmers van sintetiese malaria pigment (β-hematien). Twee nuwe Schiff-basis ligande (L2 en L4) en vier nuwe Schiff-basis komplekse (C4-C6, C8) was gesintetiseer en gekarakteriseer deur die gebruik van verskeie spektroskopiese tegnieke insluitend NMR spektroskopie, IR spektroskopie en massa spektrometrie. Die amiede biblioteek, bestaande uit twee ligande (AL1 en AL2) en sewe komplekse (AC1 tot AC7), was nog nie voorheen in die literatuur gerapporteer nie. Sikliese voltammetrie was gebruik om die ektrochemiese profiele van die ligande en komplekse te ondersoek. Die Ru(II), Rh(III) en Ir(III) komplekse kon in ‘n reeks oksidasie toestande voorkom, vanaf +1 tot +4, terwyl die Fc komplekse ‘n omkeerbare een elektron elektrochemiese respons getoon het ooreenstemmend met die Fc+/Fc redokspaar. Verder het beide biblioteke goeie tot gedeeltelike oplosbaarheid getoon; alhoewel die amiede verbindings minder oplosbaar was in vergelyking met die Schiff verbindings. Alle ligande en komplekse het goeie β-hematien inhibisie getoon in die reinigingsmiddel bepalingsproses. In die besonder het die N,N′ -Ru(II), Rh(III) en Ir(III) komplekse, vir beide biblioteke, beter β-hematien inhibisie getoon in vergelyking met hul onderskeie ligande; met die uitsondering van kinoliel Rh(III) afgeleides (C5 en AC5). In die geval van AC5 was hierdie uitsondering verwant aan die onvermoë om die kompleks voldoende te suiwer. Daar is gevind dat alle verbindings op voorgevormde β-hematien adsorbeer, met log Kads waardes wat wissel vanaf 3.7 tot 6.5, ooreenstemmend met die log Kads waardes van chlorokien en kinakrien (4.9 ± 0.3 en 4.5 ± 0.1, onderskeidelik). Spektrofotometriese titrasie in 40% (v/v) waterige DMSO (pH 7.5) het getoon dat alle verbindings met Fe(III)PPIX kan assosieer met die uitsondering van N,O′ -gekoördineerde Ru(II) komplekse weens hul swak stabiliteit. Die in vitro biologiese aktiwiteite van die Schiff-basis verbindings, teenoor die CQ-sesitiewe 3D7 en CQ-bestande Dd2 parasiete, was ook ondersoek. Die N,N′ -gekoördineerde komplekse het almal lae tot sub mikromolêre aktiwiteite getoon waarvan die Fc-bevattende verbinding, C9, die beste aktiwiteit getoon het. ‘n Beduidend korrelasie tussen in vitro biologiese aktiwiteite en assosiasie konstantes was gevind. Hierdie bevinding het aanlyding gegee tot die voorstel dat die akridien metaalkomplekse, wat in hierdie werk voorberei is, hul toksisiteit na vore bring deur 1) die remming van hemozoïen formasie, via adsorpsie aan die kristal oppervlak (soos getoon vir β-hematien), en 2) die vorming van assosiasie komplekse met die gevolglike vry Fe(III)PPIX, verantwoordelik vir die doodmaak van die parasiete. Doctoral 2021-06-07T13:36:05Z 2021-06-07T13:36:05Z 2021-03 Thesis http://hdl.handle.net/10019.1/110561 en Stellenbosch University xviii, 287 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Antimalarials Metals in medicine Heterocyclic compounds UCTD Sammy, Chandre Jade Development of new metallo-drugs for haemozoin inhibition |
| title | Development of new metallo-drugs for haemozoin inhibition |
| title_full | Development of new metallo-drugs for haemozoin inhibition |
| title_fullStr | Development of new metallo-drugs for haemozoin inhibition |
| title_full_unstemmed | Development of new metallo-drugs for haemozoin inhibition |
| title_short | Development of new metallo-drugs for haemozoin inhibition |
| title_sort | development of new metallo drugs for haemozoin inhibition |
| topic | Antimalarials Metals in medicine Heterocyclic compounds UCTD |
| url | http://hdl.handle.net/10019.1/110561 |
| work_keys_str_mv | AT sammychandrejade developmentofnewmetallodrugsforhaemozoininhibition |