Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity
<p>This thesis describes the synthesis and evaluation of cysteine-derived tetramate (pyrrolidine-2,4-dione) derivatives for the development of novel antibacterial drugs.</p> <p>Chapter 1 gives a brief overview of the history of antibiotics and clinically available antibacterial dr...
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| 格式: | Thesis |
| 语言: | English |
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2020
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| _version_ | 1826315964711436288 |
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| author | Zhang, R |
| author2 | Moloney, M |
| author_facet | Moloney, M Zhang, R |
| author_sort | Zhang, R |
| collection | OXFORD |
| description | <p>This thesis describes the synthesis and evaluation of cysteine-derived tetramate (pyrrolidine-2,4-dione) derivatives for the development of novel antibacterial drugs.</p>
<p>Chapter 1 gives a brief overview of the history of antibiotics and clinically available antibacterial drugs. It addresses the need for novel antibacterial drugs due to the emergence of bacterial resistance. While exploring different chemical approaches to tackle the problem of drug resistance, it highlights the re-emergence of natural products as a crucial source for drug development. In particular, it focuses on tetramic acid containing natural products and discusses their value in antibacterial drug discovery, their properties and synthesis. In the end, it exposes the need for optimisation of cysteine-derived tetramates due to their apparent reduction of antibacterial activity when tested in vitro in the presence of blood, hence establishing the hypotheses and aims of this project.</p>
<p>Chapter 2 describes the synthesis, structural and brief antibacterial evaluation of a library of cysteine-derived tetramates with increased hydrophilicity by incorporation of pendant heterocyclic rings. An effective synthetic protocol for accessing polar tetramate derivates is established and a computational study has developed detailed understanding of the controlling factors of the key Dieckmann cyclisation step. Direct evidence of strong metal chelation in these tetramate systems is also demonstrated.</p>
<p>Chapter 3 and 4 discuss chemical modifications on cysteine-derived tetramates to modulate their metal chelation property. Structural dependency of the metal binding ability is established, with a library of cysteine-derived tetramates exhibiting evidence for reduced metal chelation. The antibacterial activity of these tetramates is evaluated in relation with their metal binding ability.</p>
<p>Chapter 5 provides a detailed biological evaluation of the synthesised cysteine-derived tetramates with regard to their antibacterial potency, physiochemical properties and metal chelation ability. The potential for multi-targeting mechanisms coupled with a low cytotoxicity is also briefly addressed. It demonstrates the types of structural modifications possible to assess hydrophilic cysteine-derived tetramates with reduced metal chelation, while preserving their selective Gram-positive activity with MIC against MRSA < 8 μg/ml.</p> |
| first_indexed | 2024-03-07T08:18:16Z |
| format | Thesis |
| id | oxford-uuid:267a1ea5-6b76-4187-b84e-8e3fa3297fec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:35:40Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:267a1ea5-6b76-4187-b84e-8e3fa3297fec2024-12-01T19:14:12ZNatural product inspired synthesis of cysteine-derived tetramates for antibacterial activityThesishttp://purl.org/coar/resource_type/c_db06uuid:267a1ea5-6b76-4187-b84e-8e3fa3297fecChemistry, OrganicEnglishHyrax Deposit2020Zhang, RMoloney, M<p>This thesis describes the synthesis and evaluation of cysteine-derived tetramate (pyrrolidine-2,4-dione) derivatives for the development of novel antibacterial drugs.</p> <p>Chapter 1 gives a brief overview of the history of antibiotics and clinically available antibacterial drugs. It addresses the need for novel antibacterial drugs due to the emergence of bacterial resistance. While exploring different chemical approaches to tackle the problem of drug resistance, it highlights the re-emergence of natural products as a crucial source for drug development. In particular, it focuses on tetramic acid containing natural products and discusses their value in antibacterial drug discovery, their properties and synthesis. In the end, it exposes the need for optimisation of cysteine-derived tetramates due to their apparent reduction of antibacterial activity when tested in vitro in the presence of blood, hence establishing the hypotheses and aims of this project.</p> <p>Chapter 2 describes the synthesis, structural and brief antibacterial evaluation of a library of cysteine-derived tetramates with increased hydrophilicity by incorporation of pendant heterocyclic rings. An effective synthetic protocol for accessing polar tetramate derivates is established and a computational study has developed detailed understanding of the controlling factors of the key Dieckmann cyclisation step. Direct evidence of strong metal chelation in these tetramate systems is also demonstrated.</p> <p>Chapter 3 and 4 discuss chemical modifications on cysteine-derived tetramates to modulate their metal chelation property. Structural dependency of the metal binding ability is established, with a library of cysteine-derived tetramates exhibiting evidence for reduced metal chelation. The antibacterial activity of these tetramates is evaluated in relation with their metal binding ability.</p> <p>Chapter 5 provides a detailed biological evaluation of the synthesised cysteine-derived tetramates with regard to their antibacterial potency, physiochemical properties and metal chelation ability. The potential for multi-targeting mechanisms coupled with a low cytotoxicity is also briefly addressed. It demonstrates the types of structural modifications possible to assess hydrophilic cysteine-derived tetramates with reduced metal chelation, while preserving their selective Gram-positive activity with MIC against MRSA < 8 μg/ml.</p> |
| spellingShingle | Chemistry, Organic Zhang, R Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title | Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title_full | Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title_fullStr | Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title_full_unstemmed | Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title_short | Natural product inspired synthesis of cysteine-derived tetramates for antibacterial activity |
| title_sort | natural product inspired synthesis of cysteine derived tetramates for antibacterial activity |
| topic | Chemistry, Organic |
| work_keys_str_mv | AT zhangr naturalproductinspiredsynthesisofcysteinederivedtetramatesforantibacterialactivity |