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Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors
Thesis (MSc) -- Stellenbosch University, 2021
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| Format: | Thesis |
| Language: | en_ZA |
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2021
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| _version_ | 1867613806688993280 |
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| access_status_str | Open Access |
| author | Nematswerani, Ronewa |
| author2 | Blackie, M. A. L. |
| author_browse | Blackie, M. A. L. Nematswerani, Ronewa |
| author_facet | Blackie, M. A. L. Nematswerani, Ronewa |
| author_sort | Nematswerani, Ronewa |
| collection | Thesis |
| description | Thesis (MSc) -- Stellenbosch University, 2021 |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/124248 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:42:00.137Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/124248 Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors Nematswerani, Ronewa Blackie, M. A. L. van Otterlo, W. A. L. Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Glycogen --- Synthesis Glycogen synthase kinase-3 Chemical models Benzothiazoles Benzothiazoles Benzimidazoles Benzoxazole Nervous system -- Diseases Thesis (MSc) -- Stellenbosch University, 2021 ENGLISH SUMMARY: Glycogen synthase kinase 3 (GSK-3) has become a promising CNS target, since GSK-3 inhibitors have been shown to have full therapeutic potential in CNS disorders particularly in the multifactorial neuropathogenesis of Alzheimer’s disease (AD). This project focuses on the second-generation of new potential irreversible GSK-3β inhibitors, building on prior research on first-generation of compounds. Molecular modelling was carried out on the GSK-3β protein to design and identify a series of urea compounds containing suitable electrophilic warheads that have the important interactions with the binding site. The docking scores of proposed compounds were better than that of the reference GSK-3β inhibitor AR-A014418 (AstraZeneca). The library contained three sets of 1-aryl-3-(4-methoxybenzyl)ureas wherein the incorporated aryl group is the three benzazoles namely: benzothiazole, benzimidazole and benzoxazole. Incorporation of different electrophilic warheads were investigated in silico in four positions (4th, 5th, 6th and 7th) of the benzazole ring, with the potential to form an irreversible, covalent bond with nucleophilic Cys199 in the GSK-3β ATP binding pocket. Cys199 was targeted for this covalent modification as it was suggested as a new strategy for the development of novel, potent, selective GSK-3β inhibitors. Overall, the synthesis was possible on two variant positions (5th and 6th) to produce a library of novel irreversible GSK-3β and precursors with potential anti-Alzheimer’s disease activities. A total of three compounds and five precursors were successfully synthesised and were fully characterised using standard spectroscopic and analytical techniques. AFRIKAANS OPSOMMING: Glikogeen Synthase Kinase 3 (GSK-3) het ‘n belowende sentrale senuweestelsel (SS) teiken geword, aangesien GSK-3 inhibitors terapeutiese potensiaal in SS versteurings toon, veral in die multifaktoriese neuropatogenese van Alzheimersiekte. Hierdie projek fokus op die tweede generasie nuwe potensiële onomkeerbare GSK-3β remmers, wat voortbou op vorige navorsing oor die eerste generasie verbindings. Molekulêre modellering is uitgevoer op die GSK-3β proteïen om 'n reeks geskikte elektrofiliese kernkop met ureumligande te ontwerp en te identifiseer wat die belangrike interaksies met die bindingsplek het. Die koppeling tellings van voorgestelde verbindings was beter as die verwysing GSK-3β remmer AR-A014418 (AstraZeneca). Die reeks bevat drie stelle 1-aryl-3- (4-metoksibensiel) ureum verbindings, met bensotiasool, bensimidasool en bensoksasool as die onderskeidelike aryl groepe. Die biding van verskillende elektrofiele “warheads” is in silico in vier posisies (4de, 5de, 6de en 7de) van die bensasoolring ondersoek, met die moontlikheid om 'n onomkeerbare, kovalente binding met nukleofiele Cys199 in die GSK-3β ATP-bindingsholte te vorm. Cys199 is geteiken vir hierdie kovalente verandering, aangesien dit voorgestel is as 'n strategie vir die ontwikkeling van nuwe, kragtige, selektiewe GSK-3β-inhibitors. Die sintese was op twee variante posisies (5de en 6de) moontlik om 'n reeks met nuwe onomkeerbare GSK-3β-inhibitors en voorgangers te produseer met potensiële aktiwiteit teen Alzheimersiekte. Altesaam drie verbindings en vyf voorgangers is suksesvol gesintetiseer en volledig gekarakteriseer deur gebruik te maak van standaard spektroskopiese en analitiese tegnieke. Masters 2021-12-02T08:52:00Z 2022-02-22T10:19:55Z 2021-12-02T08:52:00Z 2021-12 Thesis http://hdl.handle.net/10019.1/124248 en_ZA viii, 133 pages : illustrations application/pdf |
| spellingShingle | Glycogen --- Synthesis Glycogen synthase kinase-3 Chemical models Benzothiazoles Benzothiazoles Benzimidazoles Benzoxazole Nervous system -- Diseases Nematswerani, Ronewa Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title | Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title_full | Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title_fullStr | Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title_full_unstemmed | Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title_short | Design and synthesis of benzazole ureas as proposed irreversible GSK-3β inhibitors |
| title_sort | design and synthesis of benzazole ureas as proposed irreversible gsk 3β inhibitors |
| topic | Glycogen --- Synthesis Glycogen synthase kinase-3 Chemical models Benzothiazoles Benzothiazoles Benzimidazoles Benzoxazole Nervous system -- Diseases |
| url | http://hdl.handle.net/10019.1/124248 |
| work_keys_str_mv | AT nematsweranironewa designandsynthesisofbenzazoleureasasproposedirreversiblegsk3binhibitors |