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Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities
Thesis (PhD)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867613900537593856 |
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| access_status_str | Open Access |
| author | Manye, Remofilwe Eleanor |
| author2 | Chellan, Prinessa |
| author_browse | Chellan, Prinessa Manye, Remofilwe Eleanor |
| author_facet | Chellan, Prinessa Manye, Remofilwe Eleanor |
| author_sort | Manye, Remofilwe Eleanor |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/132648 |
| institution | Stellenbosch University (South Africa) |
| last_indexed | 2026-06-10T12:43:29.841Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/132648 Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities Manye, Remofilwe Eleanor Chellan, Prinessa Ngubane, Siyabonga Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Organometallic compounds -- Physiological effect Coordination compounds -- Mechanism of action Oxidation-reduction reaction Organometallic chemistry Drug resistance in microorganisms Plasmodium falciparum -- Effect of drugs on Schiff bases -- Synthesis UCTD Thesis (PhD)--Stellenbosch University, 2025. Manye, R. E. 2025. Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/61136150-da53-4de9-8593-c46ae690cbac ENGLISH ABSTRACT: This study explores the synthesis and characterization of seven ferrocenylbenzimidazole derivatives, each with a different R group at position five of the benzimidazole moiety. Two of these derivatives are Schiff base ligands, which were subsequently metalated with Ir(III), Rh(III), and Ru(II), yielding three cationic and three neutral heterobimetallic complexes. A total of thirteen compounds were synthesized, twelve of which are novel, and one (Bz-Fc-NO2) has previously been reported. The known compound was tested against two Plasmodium falciparum strains, viz. the chloroquine (CQ)-susceptible (3D7) and the CQ-resistant strain (W2). The physicochemical properties of the synthesized compounds were investigated. These studies revealed that the cationic complexes exhibited better aqueous solubility under physiological conditions compared to their neutral counterparts. Evaluating the stability of the Schiff base ligands, which are prone to hydrolysis, revealed that Bz-Im-N,O’ readily undergoes hydrolysis. Bimetallic complexes capable of exchanging their ancillary chlorido ligand for a water molecule remained relatively stable in aqueous media. The only exception was the ruthenium cationic complex (Bz-Im-N,N’-Ru), which underwent partial aquation (8%). However, in PBS, the aquation was suppressed, likely because the high concentration of NaCl stabilized the chlorido species. In contrast, the neutral complexes (Bz-Im-N,O’-Ir, Bz-Im-N,O’-Rh and Bz-Im-N,O’-Ru) demonstrated poor solubility and stability under physiological conditions. LogP studies indicated that the ferrocenylbenzimidazole compounds were generally lipophilic (logP>0). The heteronuclear cationic complexes exhibited a balance between hydrophilicity and hydrophobicity with logP values ranging between 0.25-0.60. The logP value of Bz-Im-N,O’ could not be determined due to its rapid hydrolysis, while the logP values for the neutral complexes could not be determined due to their poor solubility in both aqueous and polar solvent, octanol. The stability of the synthesized compounds was also evaluated in the presence of glutathione (GSH), a biologically abundant thiol that can influence a compound's in vitro activity. All compounds demonstrated sufficient stability even in the presence of excess GSH. The redox profiles of these compounds were investigated using cyclic voltammetry in different media, i.e., at acidic and physiological pH, and in organic solvent. The electrochemical properties of the ferrocenylbenzimidazole complexes were analyzed, revealing that the ease of oxidation of the Fc²⁺/Fc³⁺ redox couple is significantly influenced by the nature of the substituents around the iron core, particularly the presence of electron-donating versus electron-withdrawing groups. Additionally, ligand-centred redox processes were found to be affected by the proton donor capability of the electrolyte solution as well as the presence of a second metal centre for the heterobimetallic complexes, highlighting the interplay between the ligand environment and the electrochemical conditions. The in vitro antiplasmodial activity of the synthesized ferrocenylbenzimidazole compounds was assessed against the NF54 Plasmodium falciparum strain. All compounds exhibited moderate activity, with the complex showing the greatest potency being Bz-Im-N,N’-Ru with an IC50 value of 11.81 ± 0.65 μM. This complex demonstrated a favourable balance of solubility, relative stability in aqueous media, and a logP value that optimized both hydrophilicity and lipophilicity. Preliminary in vitro studies on three breast cancer cell lines, viz. MCF-7, MDA-MB-231 and T-47D, revealed modest activity and selectivity toward specific cell lines, suggesting potential for further exploration as anticancer drug candidates. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Doctoral 2025-06-12T09:04:11Z 2025-06-12T09:04:11Z 2025-03 Thesis https://scholar.sun.ac.za/handle/10019.1/132648 Stellenbosch University 193 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Organometallic compounds -- Physiological effect Coordination compounds -- Mechanism of action Oxidation-reduction reaction Organometallic chemistry Drug resistance in microorganisms Plasmodium falciparum -- Effect of drugs on Schiff bases -- Synthesis UCTD Manye, Remofilwe Eleanor Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title | Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title_full | Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title_fullStr | Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title_full_unstemmed | Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title_short | Linking the redox profile of metallocenyl-heteroaromatic derivatives to their in vitro biological activities |
| title_sort | linking the redox profile of metallocenyl heteroaromatic derivatives to their in vitro biological activities |
| topic | Organometallic compounds -- Physiological effect Coordination compounds -- Mechanism of action Oxidation-reduction reaction Organometallic chemistry Drug resistance in microorganisms Plasmodium falciparum -- Effect of drugs on Schiff bases -- Synthesis UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/132648 |
| work_keys_str_mv | AT manyeremofilweeleanor linkingtheredoxprofileofmetallocenylheteroaromaticderivativestotheirinvitrobiologicalactivities |