Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors
- Authors: Rashamuse, Thompho Jason
- Date: 2008
- Subjects: Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4359 , http://hdl.handle.net/10962/d1005024 , Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , 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.
- Full Text:
- Date Issued: 2008
- Authors: Rashamuse, Thompho Jason
- Date: 2008
- Subjects: Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4359 , http://hdl.handle.net/10962/d1005024 , Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , 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.
- Full Text:
- Date Issued: 2008
Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2007
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2007
The effect of geography, cultivation and harvest technique on the umckalin concentration and growth of pelargonium sidoides (Geraniaceae)
- Authors: White, Andrew Graeme
- Date: 2007
- Subjects: Pelargoniums , Geraniaceae , Botany -- South Africa -- Eastern Cape , Traditional medicine -- South Africa -- Eastern Cape , Medicinal plants -- South Africa -- Eastern Cape , Coumarins
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4234 , http://hdl.handle.net/10962/d1003803 , Pelargoniums , Geraniaceae , Botany -- South Africa -- Eastern Cape , Traditional medicine -- South Africa -- Eastern Cape , Medicinal plants -- South Africa -- Eastern Cape , Coumarins
- Description: Pelargonium sidoides DC. (Geraniaceae) root extracts are used in the Eastern Cape Province of South Africa as a traditional medicine for the treatment of respiratory tract and gastro-intestinal infections. Ethanolic extracts are used globally as herbal treatments for bronchitis, asthma and as an immune system booster. Despite documented exploitation of wild populations by illegal harvesters, this species has not been awarded a protected status. The high level of harvest in the years preceding this study prompted this investigation of the prospects for sustainable root harvest through wild harvest and greenhouse cultivation. A novel method was developed for the purification of umckalin, a bioactive constituent in root extracts, such that the root umckalin concentrations of wild and cultivated plants could be quantified by HPLC. As part of the cultivation experiments, the concentration of umckalin in roots was measured for plants across part of the species’ distribution range in the Eastern Cape Province. This survey revealed that root umckalin concentrations were inversely related to the average annual rainfall of the collection site (r² = 0.94, p = 0.007) and directly related to soil pH (r² = 0.97, p = 0.002). Thus, the possibility of inducing high umckalin concentrations in greenhouse-cultivated plants was investigated by subjecting plants to rapid and prolonged water stress treatments. Two leaf applied hormone treatments (cytokinin and gibberellin) and a root competition treatment with a fast growing annual (Conyza albida) were also investigated based on the potential function of umckalin in P. sidoides plants. These five treatments did not significantly affect root umckalin concentrations compared to well-watered controls. The results of further experiments suggested that umckalin production may have been influenced by the geographical origin and genetics of plants rather than environmental variation. Following wild harvest experiments, the regrowth of replanted shoots from which a standard proportion of the root was harvested showed that water availability affected shoot survival but not root regrowth rate. Regrowth rates were low, questioning the viability of wild harvest. In contrast, greenhouse cultivated plants showed ca. six times greater growth rates, supporting the cultivation of roots to supply future market demand.
- Full Text:
- Date Issued: 2007
- Authors: White, Andrew Graeme
- Date: 2007
- Subjects: Pelargoniums , Geraniaceae , Botany -- South Africa -- Eastern Cape , Traditional medicine -- South Africa -- Eastern Cape , Medicinal plants -- South Africa -- Eastern Cape , Coumarins
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4234 , http://hdl.handle.net/10962/d1003803 , Pelargoniums , Geraniaceae , Botany -- South Africa -- Eastern Cape , Traditional medicine -- South Africa -- Eastern Cape , Medicinal plants -- South Africa -- Eastern Cape , Coumarins
- Description: Pelargonium sidoides DC. (Geraniaceae) root extracts are used in the Eastern Cape Province of South Africa as a traditional medicine for the treatment of respiratory tract and gastro-intestinal infections. Ethanolic extracts are used globally as herbal treatments for bronchitis, asthma and as an immune system booster. Despite documented exploitation of wild populations by illegal harvesters, this species has not been awarded a protected status. The high level of harvest in the years preceding this study prompted this investigation of the prospects for sustainable root harvest through wild harvest and greenhouse cultivation. A novel method was developed for the purification of umckalin, a bioactive constituent in root extracts, such that the root umckalin concentrations of wild and cultivated plants could be quantified by HPLC. As part of the cultivation experiments, the concentration of umckalin in roots was measured for plants across part of the species’ distribution range in the Eastern Cape Province. This survey revealed that root umckalin concentrations were inversely related to the average annual rainfall of the collection site (r² = 0.94, p = 0.007) and directly related to soil pH (r² = 0.97, p = 0.002). Thus, the possibility of inducing high umckalin concentrations in greenhouse-cultivated plants was investigated by subjecting plants to rapid and prolonged water stress treatments. Two leaf applied hormone treatments (cytokinin and gibberellin) and a root competition treatment with a fast growing annual (Conyza albida) were also investigated based on the potential function of umckalin in P. sidoides plants. These five treatments did not significantly affect root umckalin concentrations compared to well-watered controls. The results of further experiments suggested that umckalin production may have been influenced by the geographical origin and genetics of plants rather than environmental variation. Following wild harvest experiments, the regrowth of replanted shoots from which a standard proportion of the root was harvested showed that water availability affected shoot survival but not root regrowth rate. Regrowth rates were low, questioning the viability of wild harvest. In contrast, greenhouse cultivated plants showed ca. six times greater growth rates, supporting the cultivation of roots to supply future market demand.
- Full Text:
- Date Issued: 2007
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