- Title
- Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors
- Creator
- Rashamuse, Thompho Jason
- Subject
- Coumarins
- Subject
- Protease Inhibitors
- Subject
- HIV infections -- Treatment
- Subject
- HIV (Viruses)
- Subject
- AIDS (Disease) -- Treatment
- Subject
- Heterocyclic compounds -- Derivatives
- Date Issued
- 2008
- Date
- 2008
- Type
- Thesis
- Type
- Masters
- Type
- MSc
- Identifier
- vital:4359
- Identifier
- http://hdl.handle.net/10962/d1005024
- Identifier
- Coumarins
- Identifier
- Protease Inhibitors
- Identifier
- HIV infections -- Treatment
- Identifier
- HIV (Viruses)
- Identifier
- AIDS (Disease) -- Treatment
- Identifier
- Heterocyclic compounds -- Derivatives
- Description
- A series of the Baylis-Hillman adducts have been obtained by reacting protected O-benzylated and unprotected substituted salicylaldehydes with methyl acrylate or tertbutyl acrylate, respectively, using DABCO as catalyst. Treatment of the Baylis-Hillman adducts with HCl in a mixture of acetic acid and acetic anhydride afforded the corresponding 3-(chloromethyl)coumarin derivatives with yields of up to 94%. Similar use of HI afforded the corresponding 3-(iodomethyl)coumarins but, depending on the reaction time, the reduced 3-methyl analogues could also be obtained. Arbuzov reactions of the 3-(halomethyl)coumarin derivatives have been undertaken to afford 4-phosphorylated and 1’-phosphorylated derivatives, regioselectivity being dependent on the halide-leaving group. The 3-(chloromethyl)coumarin derivatives have been subjected to nucleophilic (SN) attack by benzylamine to give the corresponding 3- [(benzylamino)methyl]coumarin derivatives in yields of up to 74%. Further treatment of the 3-[(benzylamino)methyl]coumarin derivatives with chloroacetyl chloride afforded the chloroacetamide derivatives, which exhibit hindered rotation about the amine C(O)-N bond. The acetamide derivatives have also been subjected to Arbuzov reaction conditions to afford the phosphorylated derivatives in yields of up to 86%. In a preliminary modelling study, hydrolysed analogues of the synthesized phosphorylated derivatives have been docked into the active site of the HIV-1 protease enzyme using the Cerius-2 Ligandfit software module to provide an insight into potential receptor-ligand hydrogen bonding interactions.
- Format
- 118 p.
- Format
- Publisher
- Rhodes University
- Publisher
- Faculty of Science, Chemistry
- Language
- English
- Rights
- Rashamuse, Thompho Jason
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RU Department of Chemistry
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