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Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents
The medical success of platinum-based compounds such as cisplatin and its analogues laid the foundation for the synthesis and application of new transition metal complexes in the field of medicine. With the discovery of additional transition metal-based compounds such as ferroquine, KP1019 and NAMI-...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2022
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| _version_ | 1867614259467255808 |
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| access_status_str | Open Access |
| author | Li, Yiqun Tony |
| author2 | Smith, Gregor |
| author_browse | Li, Yiqun Tony Smith, Gregor |
| author_facet | Smith, Gregor Li, Yiqun Tony |
| author_sort | Li, Yiqun Tony |
| collection | Thesis |
| description | The medical success of platinum-based compounds such as cisplatin and its analogues laid the foundation for the synthesis and application of new transition metal complexes in the field of medicine. With the discovery of additional transition metal-based compounds such as ferroquine, KP1019 and NAMI-A, as therapeutic agents for the treatment of different diseases, the field of novel pharmacological transition metal agents continues to evolve. The constant increase in drug resistance and various undesirable side effects of current available therapies has led to the search for new strategies. Identifying novel drug candidates through utilising different metals of biological relevance is one such approach, and the main purpose of this study. New mono- and heteronuclear silicon-containing ruthenium and rhodium metal complexes based on two ligand classes, have been synthesised and characterised utilising a range of analytical and spectroscopic techniques, confirming the structural integrity. The first class of compounds was constructed from a chloroquine derivative, and was synthesised via a general Schiff-base condensation reaction. Two silicon-containing aminoquinoline ligands 2.1 and 2.2 were derived from chloroquine, modified in the lateral side chain with organosilicon moieties. Compounds 2.1 and 2.2 were further reacted with dinuclear halfsandwich transition metal precursors [Ru(Ar)(µ-Cl)Cl]i (Ar = 116 -p-iPrC6H4Me; 116 -C6H6; 116 -C6HsOCH2CH2OH), [Rh(COD)(µ-Cl)h, and [RhCp *{µ-Cl)Clh, to yield a series of neutral mononuclear Ru(II), Rh(I/111) silicon-aminoquinoline metal complexes 2.8-2.17. Ligands 2.1 and 2.2, act as monodentate donors that selectively coordinate to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. Furthermore, the molecular structures of compounds 2.2 and 2.16 were elucidated by single-crystal X-ray diffraction analysis. A second class of compounds based on the ferroquine scaffold was synthesised from ferroquine, again incorporating a organosilicon motif in the lateral side chain. Compound 3.6 was further reacted with the afore-mentioned Ru and Rh dinuclear half-sandwich transition metal precursors to yield a series of neutral heteronuclear Ru(II) and Rh(I/111) siliconcontaining ferrocenyl aminoquinoline metal complexes 3.7-3.11 isolated in moderate yields. Compound 3.6 coordinates to the metal in a similar manner to ligands 2.1 and 2.2 (via the quinoline nitrogen), and all the complexes 3.7-3.11 were fully characterised confirming the structural integrity. Furthermore, the molecular structure of compound 3.6 was elucidated by iii single-crystal X-ray diffraction analysis, showing the ferrocene and organosilicon motifs incorporated into the lateral side chain of the quinoline scaffold. The in vitro pharmacological activities of the synthesised compounds were established against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malarial parasite, Plasmodium falciparum, and against the pathogenic bacterium, Mycobacterium tuberculosis H31Rv, as well as an oesophageal (WHCO 1) cancer cell line. All compounds were found to exhibit moderate to high antiplasmodial activities against the NF54 and Dd2 P. falciparum strains, with IC50 values in the nanomolar range for the ferroquine-derivatised series. The heterometallic series shows superior biological activity, suggesting that different metals may interact with multiple biological targets, providing chemical diversity, thus improving the physicochemical properties. The IC50 values of compounds 3.7-3.11 are comparable to ferroquine, and in selective cases, better than the current clinical antiplasmodial agent chloroquine. Furthermore, the more lipophilic ferroquine-derivatised series, displayed better inhibition of 13-haematin through superior accumulation in the food vacuole of the parasite, and therefore better at killing the malaria parasite. All compounds exhibited weak to moderate antitumour activities. The studies also showed that the ruthenium metal complexes generally display better activity in comparison with the rhodium complexes, and the compounds containing a 3-carbon chain spacer generally show better activity in comparison to those containing a I-carbon spacer. The presence of the metal moiety did not significantly enhance the biological activities in comparison with the organic ligands. In general, all compounds exhibited weak to moderate antimycobacterial activities against M tuberculosis H37Rv strain. Overall, the turbidimetric solubility assay data suggests that these newly synthesised silicon-containing chloroquine and ferroquine derivatives are relatively good drug candidates for in vitro pharmacological testing. All compounds showed moderate solubility in the aqueous PBS buffer. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/36618 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:49:12.208Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/36618 Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents Li, Yiqun Tony Smith, Gregor Chibale, Kelly chemistry The medical success of platinum-based compounds such as cisplatin and its analogues laid the foundation for the synthesis and application of new transition metal complexes in the field of medicine. With the discovery of additional transition metal-based compounds such as ferroquine, KP1019 and NAMI-A, as therapeutic agents for the treatment of different diseases, the field of novel pharmacological transition metal agents continues to evolve. The constant increase in drug resistance and various undesirable side effects of current available therapies has led to the search for new strategies. Identifying novel drug candidates through utilising different metals of biological relevance is one such approach, and the main purpose of this study. New mono- and heteronuclear silicon-containing ruthenium and rhodium metal complexes based on two ligand classes, have been synthesised and characterised utilising a range of analytical and spectroscopic techniques, confirming the structural integrity. The first class of compounds was constructed from a chloroquine derivative, and was synthesised via a general Schiff-base condensation reaction. Two silicon-containing aminoquinoline ligands 2.1 and 2.2 were derived from chloroquine, modified in the lateral side chain with organosilicon moieties. Compounds 2.1 and 2.2 were further reacted with dinuclear halfsandwich transition metal precursors [Ru(Ar)(µ-Cl)Cl]i (Ar = 116 -p-iPrC6H4Me; 116 -C6H6; 116 -C6HsOCH2CH2OH), [Rh(COD)(µ-Cl)h, and [RhCp *{µ-Cl)Clh, to yield a series of neutral mononuclear Ru(II), Rh(I/111) silicon-aminoquinoline metal complexes 2.8-2.17. Ligands 2.1 and 2.2, act as monodentate donors that selectively coordinate to the transition metals via the quinoline nitrogen of the aminoquinoline scaffold. Furthermore, the molecular structures of compounds 2.2 and 2.16 were elucidated by single-crystal X-ray diffraction analysis. A second class of compounds based on the ferroquine scaffold was synthesised from ferroquine, again incorporating a organosilicon motif in the lateral side chain. Compound 3.6 was further reacted with the afore-mentioned Ru and Rh dinuclear half-sandwich transition metal precursors to yield a series of neutral heteronuclear Ru(II) and Rh(I/111) siliconcontaining ferrocenyl aminoquinoline metal complexes 3.7-3.11 isolated in moderate yields. Compound 3.6 coordinates to the metal in a similar manner to ligands 2.1 and 2.2 (via the quinoline nitrogen), and all the complexes 3.7-3.11 were fully characterised confirming the structural integrity. Furthermore, the molecular structure of compound 3.6 was elucidated by iii single-crystal X-ray diffraction analysis, showing the ferrocene and organosilicon motifs incorporated into the lateral side chain of the quinoline scaffold. The in vitro pharmacological activities of the synthesised compounds were established against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the malarial parasite, Plasmodium falciparum, and against the pathogenic bacterium, Mycobacterium tuberculosis H31Rv, as well as an oesophageal (WHCO 1) cancer cell line. All compounds were found to exhibit moderate to high antiplasmodial activities against the NF54 and Dd2 P. falciparum strains, with IC50 values in the nanomolar range for the ferroquine-derivatised series. The heterometallic series shows superior biological activity, suggesting that different metals may interact with multiple biological targets, providing chemical diversity, thus improving the physicochemical properties. The IC50 values of compounds 3.7-3.11 are comparable to ferroquine, and in selective cases, better than the current clinical antiplasmodial agent chloroquine. Furthermore, the more lipophilic ferroquine-derivatised series, displayed better inhibition of 13-haematin through superior accumulation in the food vacuole of the parasite, and therefore better at killing the malaria parasite. All compounds exhibited weak to moderate antitumour activities. The studies also showed that the ruthenium metal complexes generally display better activity in comparison with the rhodium complexes, and the compounds containing a 3-carbon chain spacer generally show better activity in comparison to those containing a I-carbon spacer. The presence of the metal moiety did not significantly enhance the biological activities in comparison with the organic ligands. In general, all compounds exhibited weak to moderate antimycobacterial activities against M tuberculosis H37Rv strain. Overall, the turbidimetric solubility assay data suggests that these newly synthesised silicon-containing chloroquine and ferroquine derivatives are relatively good drug candidates for in vitro pharmacological testing. All compounds showed moderate solubility in the aqueous PBS buffer. 2022-07-05T06:40:43Z 2022-07-05T06:40:43Z 2013 2022-07-05T06:39:57Z Master Thesis Masters MSc http://hdl.handle.net/11427/36618 eng application/pdf Department of Chemistry Faculty of Science |
| spellingShingle | chemistry Li, Yiqun Tony Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| thesis_degree_str | Master's |
| title | Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| title_full | Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| title_fullStr | Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| title_full_unstemmed | Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| title_short | Synthesis, characterisation and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor and antimycobacterial agents |
| title_sort | synthesis characterisation and pharmacological evaluation of silicon containing aminoquinoline organometallic complexes as antiplasmodial antitumor and antimycobacterial agents |
| topic | chemistry |
| url | http://hdl.handle.net/11427/36618 |
| work_keys_str_mv | AT liyiquntony synthesischaracterisationandpharmacologicalevaluationofsiliconcontainingaminoquinolineorganometalliccomplexesasantiplasmodialantitumorandantimycobacterialagents |