- Title
- Application of Baylis-Hillman methodology in the synthesis of HIV-1 enzyme inhibitors
- Creator
- Manyeruke, Meloddy Hlatini
- ThesisAdvisor
- Kaye, Perry T
- Subject
- HIV infections
- Subject
- Enzyme inhibitors
- Subject
- AZT (Drug)
- Subject
- Bioconjugates
- Date
- 2015
- Type
- Thesis
- Type
- Masters
- Type
- MSc
- Identifier
- vital:4540
- Identifier
- http://hdl.handle.net/10962/d1017920
- Description
- The application of Baylis-Hillman methodology has afforded access to a range of β-hydroxypropionate ester-AZT conjugates as potential dual-action HIV-1 IN/RT inhibitors. Two families comprising a total of nine β-hydroxypropionate ester-AZT conjugates were synthesised. The first family was accessed using O-benzylated salicylaldehydes and methyl acrylate and the second from unprotected salicylaldehydes using tert-butyl acrylate as the activated alkene. Spectroscopic methods were employed to fully characterize the compounds. Propargylation of the respective Baylis-Hillman adducts was achieved via conjugate addition of propargylamine. The resulting products were then employed in Cu(I)-catalysed “click” reactions with azidothymidine (AZT) to yield the desired β-hydroxypropionate ester-AZT conjugates. Exploratory studies were also conducted to access 4-hydroxycoumarins from Baylis-Hillman derived adducts and to construct customized chiral Baylis-Hillman reaction sites. Many 4- hydroxycoumarins are known to exhibit a wide range of biological activities, and extending Baylis-Hillman methodology to access these systems is an important challenge. Two approaches were investigated. The first involved the formation of a 4-phthalimidocoumarin, aromatisation and hydrolysis of which was expected to lead to the 4-hydroxycoumarin target. The second, a variation of the first, involved the use of 4-(chrolomethyl)coumarin intermediates. Unfortunately, while various intermediates were prepared and characterised, neither approach led ultimately to the desired targets. N-substituted borneol-10-sulfonamides were constructed from camphor-10- sulfonyl chloride as chiral Baylis-Hillman reaction sites. In a preliminary study, however, none of the N-substituted borneol-10-sulfonamides exhibited Baylis-Hillman catalytic activity.
- Format
- 110 p, pdf
- Publisher
- Rhodes University, Faculty of Science, Chemistry
- Language
- English
- Rights
- Manyeruke, Meloddy Hlatini
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