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Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer
Thesis (PhD)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University, 2021
2021
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| _version_ | 1867613732327129088 |
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| access_status_str | Open Access |
| author | Hay, Jonathan Bruce |
| author2 | Blackie, Margaret |
| author_browse | Blackie, Margaret Hay, Jonathan Bruce |
| author_facet | Blackie, Margaret Hay, Jonathan Bruce |
| author_sort | Hay, Jonathan Bruce |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/124193 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:40:49.380Z |
| 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, 2021 |
| publisherStr | Stellenbosch : Stellenbosch University, 2021 |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/124193 Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer Hay, Jonathan Bruce Blackie, Margaret Willem, van Otterlo Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Chemistry, Organic -- Synthesis Benzoic acid Hybrid compounds Plasmodium falciparum Hybrid Inhibitors UCTD Malaria -- Chemotherapy Cancer -- Chemotherapy Thesis (PhD)--Stellenbosch University, 2021. ENGLISH ABSTRACT: In this study, the design and synthesis of a series of 12 known and novel 2,4-substituted benzofuran and benzothiophene derivatives, 4 known 4-aminoquinolines and 16 novel dual heterocyclic hybrids are described. The series of hybrid compounds was successfully synthesized by amide and ester functional group couplings of benzofuran carboxylic acid derivatives with 4-aminoquinolines, and similarly, benzothiophene carboxylic acids with 4- aminoquinolines. In addition, a short investigation into the synthesis of symmetrical heterocycles successfully produced two novel bis-benzothiophene compounds. These known and novel heterocycle and hybrid compounds were screened in vitro against the chloroquine sensitive NF54 strain of Plasmodium falciparum to evaluate their potential as antiplasmodial agents. The results from the biological screening are presented and discussed for the heterocycles and indicated that the benzofuran and benzothiophene analogues exhibited poor antiplasmodial activity (IC50: >10 μM). In contrast, the entire series of novel dual heterocyclic compounds exhibited good antiplasmodial activity with IC50 values between 0.089 μM and 2.75 μM concentrations, with the four known 4-aminoquinolines showing antiplasmodial activity between 0.090 μM and 5.84 μM concentrations. A small group of hybrids and the two symmetrical compounds were also subjected to preliminary in vitro anticancer screening against WHCO1 oesophageal cancer cells to evaluate whether there was any potential for these types of compounds to be cancer inhibitors. Results obtained from the preliminary screening indicated that there was indeed anticancer activity with IC50 values below 10 μM, however there are still some results outstanding to confirm the initial data. This study has provided results in support of dual heterocyclic hybrid compounds based on benzofuran/quinoline and benzothiophene/quinoline scaffolds, that have the potential to inhibit Plasmodium falciparum and can be viable scaffolds for designing new antimalarial drugs. AFRIKAANS OPSOMMING: In hierdie studie word die ontwerp en sintese van 'n reeks van 12 bekende en nuwe 2,4- gesubstitueerde bensofuran- en bensotiofenederivate, 4 bekende 4-aminokinoliene en 16 nuwe dubbele heterosikliese basters. Die reeks baster-verbindings is suksesvol gesintetiseer deur amied- en ester funksionele groep koppeling van bensofuran-karboksiel suur afgeleides met 4-aminokinoliene, en insgelyks, bensotiofeenkarboksielsure met 4-aminokinoliene. Daarbenewens het 'n kort ondersoek na die sintese van simmetriese heterosiklusse twee nuwe bis-bensotiofeen verbindings suksesvol opgelewer. Hierdie bekende en nuwe heterosiklus- en basterverbindings is in vitro gekeur teen die chloorkiengevoelige NF54-stam van Plasmodium falciparum om hul potensiaal as antiplasmodiale middels te evalueer. Die resultate van die biologiese sifting word aangebied en bespreek vir die heterosiklusse wat daarop dui dat die bensofuraan- en bensotiofeenanaloë swak antiplasmodiale aktiwiteit vertoon (IC50:> 10 μM). Daarenteen vertoon die hele reeks nuwe dubbele heterosikliese verbindings goeie antiplasmodiale aktiwiteit met IC50-waardes tussen 0,089 μM en 2,75 μM konsentrasies, met die vier bekende 4-aminokinoliene wat antiplasmodiale aktiwiteit vertoon tussen 0,090 μM en 5,84 μM konsentrasies. 'n Klein groepie basters en die twee simmetriese verbindings is ook onderwerp aan voorlopige in-vitro-antikankersifting teen WHCO1-slukdermkankerselle om te evalueer of die moontlikheid bestaan dat hierdie tipe verbindings kankerinhibeerders kan wees. Resultate verkry uit die voorlopige keuring het aangedui dat daar wel antikankeraktiwiteit met IC50 onder 10 μM was, maar daar is nog steeds uitstaande resultate om die aanvanklike data te bevestig. Hierdie studie het resultate gelewer ter ondersteuning van dubbele heterosikliese baster-verbindings gebaseer op bensofuran / kinolien en bensotiofeen / kinolien steiers, wat die potensiaal het om Plasmodium falciparum te inhibeer en lewensvatbare steiers kan wees vir die ontwerp van nuwe malaria-middels. Doctorate 2021-06-01T10:00:35Z 2022-02-22T10:15:30Z 2022-02-23T03:00:07Z 2021-12 Thesis http://hdl.handle.net/10019.1/124193 en_ZA Stellenbosch University xi, 173 pages : illustrations application/pdf Stellenbosch : Stellenbosch University, 2021 |
| spellingShingle | Chemistry, Organic -- Synthesis Benzoic acid Hybrid compounds Plasmodium falciparum Hybrid Inhibitors UCTD Malaria -- Chemotherapy Cancer -- Chemotherapy Hay, Jonathan Bruce Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title | Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title_full | Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title_fullStr | Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title_full_unstemmed | Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title_short | Design and synthesis of dual-heterocyclic hybrid inhibitors for malaria and cancer |
| title_sort | design and synthesis of dual heterocyclic hybrid inhibitors for malaria and cancer |
| topic | Chemistry, Organic -- Synthesis Benzoic acid Hybrid compounds Plasmodium falciparum Hybrid Inhibitors UCTD Malaria -- Chemotherapy Cancer -- Chemotherapy |
| url | http://hdl.handle.net/10019.1/124193 |
| work_keys_str_mv | AT hayjonathanbruce designandsynthesisofdualheterocyclichybridinhibitorsformalariaandcancer |