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Structure activity and structure property relationships of antimalarial imidazopyridazines
Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s popula...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2020
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| _version_ | 1867614144509771776 |
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| access_status_str | Open Access |
| author | Centani, Luyanda |
| author2 | Chibale, Kelly |
| author_browse | Centani, Luyanda Chibale, Kelly |
| author_facet | Chibale, Kelly Centani, Luyanda |
| author_sort | Centani, Luyanda |
| collection | Thesis |
| description | Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s population is exposed to varying degrees of malaria. Malaria is caused by different species of the Plasmodium genus and the disease is vector-borne. The disease may be cured if diagnosed early. Most drugs that were once effective in the treatment of malaria have become ineffective due to the emergence of resistance, which has become the main driving force behind efforts to discover and develop new drugs able to circumvent the resistance. Imidazopyridazines have been shown to have potent antiplasmodium activity. The lead compound MMV652103 has been shown to display potent activity against the multidrug resistant K1 strain and the drug sensitive NF54 strain of the human malaria parasite Plasmodium falciparum. However, the majority of the antimalarial imidazopyridazine compounds evaluated to date have solubility and off-target human ether-a-go-go-related gene (hERG) potassium ion channel liabilities. Towards improving solubility and de-risking the hERG liability, a series of analogues was designed and synthesised. Structure-Activity Relationship (SAR) and Structure-Property Relationship (SPR) studies aimed at retaining the good antiplasmodium activity while improving solubility and reducing hERG channel inhibition, were conducted. Previous studies conducted on this series of imidazopyridazines have shown that incorporation of hydrogen bond donors or acceptors resulted in improving solubility and hERG channel inhibition. While the lead compound MMV652103 at pH 6.5 has a sub-optimal solubility of 5 µM, all target compounds showed an improvement in solubility. Five analogues 59, 78, 84, 85, and 86 exhibiting impressive in vitro asexual blood stage antiplasmodium potency (IC50< 100 nM) and aqueous solubility (> 200 µM) were identified from the study. The identified compounds also displayed good activity against the sexual late-stage gametocytes, the transmissible forms of the parasite. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/31315 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:47:22.576Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2020 |
| publishDateRange | 2020 |
| publishDateSort | 2020 |
| 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:11427/31315 Structure activity and structure property relationships of antimalarial imidazopyridazines Centani, Luyanda Chibale, Kelly chemistry Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s population is exposed to varying degrees of malaria. Malaria is caused by different species of the Plasmodium genus and the disease is vector-borne. The disease may be cured if diagnosed early. Most drugs that were once effective in the treatment of malaria have become ineffective due to the emergence of resistance, which has become the main driving force behind efforts to discover and develop new drugs able to circumvent the resistance. Imidazopyridazines have been shown to have potent antiplasmodium activity. The lead compound MMV652103 has been shown to display potent activity against the multidrug resistant K1 strain and the drug sensitive NF54 strain of the human malaria parasite Plasmodium falciparum. However, the majority of the antimalarial imidazopyridazine compounds evaluated to date have solubility and off-target human ether-a-go-go-related gene (hERG) potassium ion channel liabilities. Towards improving solubility and de-risking the hERG liability, a series of analogues was designed and synthesised. Structure-Activity Relationship (SAR) and Structure-Property Relationship (SPR) studies aimed at retaining the good antiplasmodium activity while improving solubility and reducing hERG channel inhibition, were conducted. Previous studies conducted on this series of imidazopyridazines have shown that incorporation of hydrogen bond donors or acceptors resulted in improving solubility and hERG channel inhibition. While the lead compound MMV652103 at pH 6.5 has a sub-optimal solubility of 5 µM, all target compounds showed an improvement in solubility. Five analogues 59, 78, 84, 85, and 86 exhibiting impressive in vitro asexual blood stage antiplasmodium potency (IC50< 100 nM) and aqueous solubility (> 200 µM) were identified from the study. The identified compounds also displayed good activity against the sexual late-stage gametocytes, the transmissible forms of the parasite. 2020-02-25T11:34:32Z 2020-02-25T11:34:32Z 2019 2020-02-25T06:32:19Z Master Thesis Masters MSc http://hdl.handle.net/11427/31315 eng application/pdf Department of Chemistry Faculty of Science |
| spellingShingle | chemistry Centani, Luyanda Structure activity and structure property relationships of antimalarial imidazopyridazines |
| thesis_degree_str | Master's |
| title | Structure activity and structure property relationships of antimalarial imidazopyridazines |
| title_full | Structure activity and structure property relationships of antimalarial imidazopyridazines |
| title_fullStr | Structure activity and structure property relationships of antimalarial imidazopyridazines |
| title_full_unstemmed | Structure activity and structure property relationships of antimalarial imidazopyridazines |
| title_short | Structure activity and structure property relationships of antimalarial imidazopyridazines |
| title_sort | structure activity and structure property relationships of antimalarial imidazopyridazines |
| topic | chemistry |
| url | http://hdl.handle.net/11427/31315 |
| work_keys_str_mv | AT centaniluyanda structureactivityandstructurepropertyrelationshipsofantimalarialimidazopyridazines |