Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases
<p>The research described in this thesis concerns the development of novel small molecule inhibitors of biologically relevant nucleophilic hydrolases, i.e. β-lactamases, SARS-CoV-2 main protease (Mpro) and elastases, which are therapeutic targets for combatting public health threats associated...
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| Формат: | Диссертация |
| Язык: | English |
| Опубликовано: |
2024
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| _version_ | 1826316936817934336 |
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| author | Gayatri |
| author2 | Schofield, C |
| author_facet | Schofield, C Gayatri |
| author_sort | Gayatri |
| collection | OXFORD |
| description | <p>The research described in this thesis concerns the development of novel small molecule inhibitors of biologically relevant nucleophilic hydrolases, i.e. β-lactamases, SARS-CoV-2 main protease (Mpro) and elastases, which are therapeutic targets for combatting public health threats associated with antimicrobial resistance, the COVID-19 pandemic and chronic inflammatory diseases, respectively. The work focused on the synthesis and structure activity relationship (SAR) exploration of two small molecule templates, i.e. C6-functionalised benzoxaboroles and thiophene-fused γ-lactams. These templates have potential to inhibit nucleophilic enzymes by covalent reaction with nucleophilic active site residues, owing to the presence of their electrophilic boron or γ-lactam carbonyl groups, respectively.</p>
<p><strong>Chapter 2</strong> describes the synthesis of a set of C6-functionalised benzoxaborole derivatives and their biochemical investigation as inhibitors of clinically relevant serine β-lactamases (SBLs) and metallo β-lactamases (MBLs). The results reveal C6-sulfonamide-substituted benzoxaboroles as promising SBL and MBL inhibitors, subject to further optimisation. <strong>Chapter 3</strong> describes studies evaluating the potential of the thiophene-fused γ-lactam scaffold for covalent inhibition of SARS- CoV-2 Mpro. A set of α- and N-substituted γ-lactams was synthesised; subsequent SAR and mass spectrometry studies indicate that thiophene-fused γ-lactams can effectively inhibit Mpro <em>via</em> reversible covalent reaction with the nucleophilic Cys145. <strong>Chapter 4</strong> extends inhibition studies of thiophene-fused γ-lactam and benzoxaborole derivatives to SAR studies on porcine pancreatic elastase (PPE) and human neutrophil elastase (HNE). The results lay groundwork for the development of benzoxaborole-based compounds as elastase inhibitors. The PPE inhibitory activity of both thiophene-fused γ-lactams and C6-functionalised benzoxaboroles is further supported by mass spectrometry and crystallographic studies which provide insights into their mechanisms of inhibition involving covalent reaction with the nucleophilic Ser195.</p>
<p>Overall, the work presented in this thesis identifies benzoxaboroles and thiophene-fused γ-lactam compounds as promising templates for development of potent covalently reacting small molecule inhibitors of biologically important nucleophilic hydrolases.</p> |
| first_indexed | 2025-02-19T04:32:16Z |
| format | Thesis |
| id | oxford-uuid:dd7cff67-a6d9-4268-9488-dbf554e9fbe6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:32:16Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:dd7cff67-a6d9-4268-9488-dbf554e9fbe62025-01-03T15:08:55ZSynthesis and development of novel small molecule inhibitors of nucleophilic hydrolasesThesishttp://purl.org/coar/resource_type/c_db06uuid:dd7cff67-a6d9-4268-9488-dbf554e9fbe6Protease inhibitorsDrug interactionsEnzyme inhibitorsOrganic compounds--SynthesisChemistry, OrganicMechanism of action (Biochemistry)Binding sites (Biochemistry)Structure-activity relationships (Biochemistry)Dose-response relationship (Biochemistry)Pharmaceutical chemistryEnglishHyrax Deposit2024GayatriSchofield, C<p>The research described in this thesis concerns the development of novel small molecule inhibitors of biologically relevant nucleophilic hydrolases, i.e. β-lactamases, SARS-CoV-2 main protease (Mpro) and elastases, which are therapeutic targets for combatting public health threats associated with antimicrobial resistance, the COVID-19 pandemic and chronic inflammatory diseases, respectively. The work focused on the synthesis and structure activity relationship (SAR) exploration of two small molecule templates, i.e. C6-functionalised benzoxaboroles and thiophene-fused γ-lactams. These templates have potential to inhibit nucleophilic enzymes by covalent reaction with nucleophilic active site residues, owing to the presence of their electrophilic boron or γ-lactam carbonyl groups, respectively.</p> <p><strong>Chapter 2</strong> describes the synthesis of a set of C6-functionalised benzoxaborole derivatives and their biochemical investigation as inhibitors of clinically relevant serine β-lactamases (SBLs) and metallo β-lactamases (MBLs). The results reveal C6-sulfonamide-substituted benzoxaboroles as promising SBL and MBL inhibitors, subject to further optimisation. <strong>Chapter 3</strong> describes studies evaluating the potential of the thiophene-fused γ-lactam scaffold for covalent inhibition of SARS- CoV-2 Mpro. A set of α- and N-substituted γ-lactams was synthesised; subsequent SAR and mass spectrometry studies indicate that thiophene-fused γ-lactams can effectively inhibit Mpro <em>via</em> reversible covalent reaction with the nucleophilic Cys145. <strong>Chapter 4</strong> extends inhibition studies of thiophene-fused γ-lactam and benzoxaborole derivatives to SAR studies on porcine pancreatic elastase (PPE) and human neutrophil elastase (HNE). The results lay groundwork for the development of benzoxaborole-based compounds as elastase inhibitors. The PPE inhibitory activity of both thiophene-fused γ-lactams and C6-functionalised benzoxaboroles is further supported by mass spectrometry and crystallographic studies which provide insights into their mechanisms of inhibition involving covalent reaction with the nucleophilic Ser195.</p> <p>Overall, the work presented in this thesis identifies benzoxaboroles and thiophene-fused γ-lactam compounds as promising templates for development of potent covalently reacting small molecule inhibitors of biologically important nucleophilic hydrolases.</p> |
| spellingShingle | Protease inhibitors Drug interactions Enzyme inhibitors Organic compounds--Synthesis Chemistry, Organic Mechanism of action (Biochemistry) Binding sites (Biochemistry) Structure-activity relationships (Biochemistry) Dose-response relationship (Biochemistry) Pharmaceutical chemistry Gayatri Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title | Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title_full | Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title_fullStr | Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title_full_unstemmed | Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title_short | Synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| title_sort | synthesis and development of novel small molecule inhibitors of nucleophilic hydrolases |
| topic | Protease inhibitors Drug interactions Enzyme inhibitors Organic compounds--Synthesis Chemistry, Organic Mechanism of action (Biochemistry) Binding sites (Biochemistry) Structure-activity relationships (Biochemistry) Dose-response relationship (Biochemistry) Pharmaceutical chemistry |
| work_keys_str_mv | AT gayatri synthesisanddevelopmentofnovelsmallmoleculeinhibitorsofnucleophilichydrolases |