Application of Baylis-Hillman methodology in the synthesis of HIV-1 enzyme inhibitors
- Authors: Manyeruke, Meloddy Hlatini
- Date: 2015
- Subjects: HIV infections , Enzyme inhibitors , AZT (Drug) , Bioconjugates
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4540 , 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.
- Full Text:
- Authors: Manyeruke, Meloddy Hlatini
- Date: 2015
- Subjects: HIV infections , Enzyme inhibitors , AZT (Drug) , Bioconjugates
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4540 , 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.
- Full Text:
Design, development and evaluation of novel lead compounds as HIV-1 enzyme inhibitors
- Authors: Sekgota, Khethobole Cassius
- Date: 2015
- Subjects: Enzyme inhibitors , Viruses -- Reproduction , HIV (Viruses)
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4546 , http://hdl.handle.net/10962/d1017926
- Description: This project has been concerned with the application of the Baylis-Hillman methodology to the synthesis of medicinally important diketo acid analogues (cinnamate ester-AZT conjugates and 3-hydroxy ester-AZT conjugates) as dual-action HIV-1 IN/RT inhibitors; and on exploratory studies in the preparation of 3-(amidomethyl)-(1H)-2-quinolones as PR inhibitors; and (1H)-2- quinolone-AZT conjugates as dual action IN/RT inhibitors. A series of Baylis-Hillman adducts has been prepared, typically in moderate to excellent yield, by reacting 2-nitrobenzaldehyde with methyl acrylate, ethyl acrylate and methyl vinyl ketone in the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO). Subsequently, various transformations that include conjugate addition of primary and secondary amines to the α,ß-unsaturated moiety to obtain 2- (aminomethyl)-3-hydroxy-3-(2-nitrophenyl)propanoate derivatives, effective SN2´ substitution of the BH ß-hydroxy by a Vilsmeier-Haack in situ-generated chloride to afford Baylis-Hillman allyl chlorides, iron in acetic acid-catalyzed cyclisation to 3-acetoxymethyl-(1H)-2-quinolone derivatives were achieved. Thus, using the Baylis-Hillman methodology, two nuanced classes of diketo acid analogues were constructed. These involved conjugating appropriate propargylamine derivatives with AZT using the „click‟ reaction. In an exploratory study, the quinolone derivative, precisely 3-acetoxymethyl- (1H)-quinol-2-one, was transformed into 3-hydroxymethyl-(1H)-quinol-2-one using potassium carbonate in a mixture of methanol and water (1:1). Following successful hydrolysis, the resulting alcohol was transformed to the corresponding chloride, 3-chloromethyl-(1H)-quinol-2- one, using thionyl chloride. Subsequent nucleophilic substitution afforded 3-(aminomethyl)- (1H)-2-quinolone derivatives which were subsequently transformed to 3-(amidomethyl)-(1H)-2- quinolones; and 3-[(propargylamino)-methyl]-(1H)-quinol-2-one as precursors to quinolone- AZT derivatives. All compounds were characterized by NMR, IR, and where appropriate, high resolution MS
- Full Text:
- Authors: Sekgota, Khethobole Cassius
- Date: 2015
- Subjects: Enzyme inhibitors , Viruses -- Reproduction , HIV (Viruses)
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4546 , http://hdl.handle.net/10962/d1017926
- Description: This project has been concerned with the application of the Baylis-Hillman methodology to the synthesis of medicinally important diketo acid analogues (cinnamate ester-AZT conjugates and 3-hydroxy ester-AZT conjugates) as dual-action HIV-1 IN/RT inhibitors; and on exploratory studies in the preparation of 3-(amidomethyl)-(1H)-2-quinolones as PR inhibitors; and (1H)-2- quinolone-AZT conjugates as dual action IN/RT inhibitors. A series of Baylis-Hillman adducts has been prepared, typically in moderate to excellent yield, by reacting 2-nitrobenzaldehyde with methyl acrylate, ethyl acrylate and methyl vinyl ketone in the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO). Subsequently, various transformations that include conjugate addition of primary and secondary amines to the α,ß-unsaturated moiety to obtain 2- (aminomethyl)-3-hydroxy-3-(2-nitrophenyl)propanoate derivatives, effective SN2´ substitution of the BH ß-hydroxy by a Vilsmeier-Haack in situ-generated chloride to afford Baylis-Hillman allyl chlorides, iron in acetic acid-catalyzed cyclisation to 3-acetoxymethyl-(1H)-2-quinolone derivatives were achieved. Thus, using the Baylis-Hillman methodology, two nuanced classes of diketo acid analogues were constructed. These involved conjugating appropriate propargylamine derivatives with AZT using the „click‟ reaction. In an exploratory study, the quinolone derivative, precisely 3-acetoxymethyl- (1H)-quinol-2-one, was transformed into 3-hydroxymethyl-(1H)-quinol-2-one using potassium carbonate in a mixture of methanol and water (1:1). Following successful hydrolysis, the resulting alcohol was transformed to the corresponding chloride, 3-chloromethyl-(1H)-quinol-2- one, using thionyl chloride. Subsequent nucleophilic substitution afforded 3-(aminomethyl)- (1H)-2-quinolone derivatives which were subsequently transformed to 3-(amidomethyl)-(1H)-2- quinolones; and 3-[(propargylamino)-methyl]-(1H)-quinol-2-one as precursors to quinolone- AZT derivatives. All compounds were characterized by NMR, IR, and where appropriate, high resolution MS
- Full Text:
Studies towards the development of novel antimalarial agents
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
Studies towards the development of novel HIV-1 integrase inhibitors
- Authors: Lee, Yi-Chen
- Date: 2010
- Subjects: HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Nuclear magnetic resonance , Heterocyclic compounds -- Derivatives , Enzyme inhibitors , Chemical inhibitors , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4357 , http://hdl.handle.net/10962/d1005022 , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Nuclear magnetic resonance , Heterocyclic compounds -- Derivatives , Enzyme inhibitors , Chemical inhibitors , Quinoline
- Description: The project has focused on the preparation of several series of compounds designed as potential HIV-1 integrase inhibitors. Various 2-nitrobenzaldehydes have been reacted with two activated alkenes, methyl vinyl ketone (MVK) and methyl acrylate, under Baylis-Hillman conditions to afford α-methylene-β-hydroxylalkyl derivatives in moderate to excellent yields. The reactions were conducted using the tertiary amine catalysts, 1,4-diazabicyclo[2.2.2]octane(DABCO) or 3-hydroxyquinuclidine (3-HQ) with chloroform as solvent, and yields were optimised by varying the catalyst, reagent concentrations and the reaction time. Reductive cyclization of the Baylis-Hillman adducts via catalytic hydrogenation, using 10% palladiumon-carbon catalyst in ethanol, afforded quinoline and quinoline N-oxide derivatives. In some cases “acyclic” reduction products were also isolated. Reaction of the Baylis-Hillman MVK adducts with HCl, has resulted in effective nucleophilic (SN’) displacement of the hydroxyl group to afford allylic chloride derivatives. Direct substitution of these chloro derivatives by secondary or primary amines, followed by catalytic hydrogenation gave quinoline derivatives containing a 3-aminomethyl substituent. The Baylis-Hillman ester adducts obtained from reaction with methyl acrylate were treated directly with various amines to give diastereomeric conjugate addition products. Reactions with piperazine gave N,N’-disubstituted piperazine products. The piperidine derivatives have been dehydrated to give cinnamate esters in moderate yields. The products, which have all been satisfactorily characterised by elemental (HRMS) and spectroscopic (1- and 2-D NMR) analysis, constitute a “library” of compounds for in silico and in vitro studies as potential HIV integrase inhibitors.
- Full Text:
- Authors: Lee, Yi-Chen
- Date: 2010
- Subjects: HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Nuclear magnetic resonance , Heterocyclic compounds -- Derivatives , Enzyme inhibitors , Chemical inhibitors , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4357 , http://hdl.handle.net/10962/d1005022 , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Nuclear magnetic resonance , Heterocyclic compounds -- Derivatives , Enzyme inhibitors , Chemical inhibitors , Quinoline
- Description: The project has focused on the preparation of several series of compounds designed as potential HIV-1 integrase inhibitors. Various 2-nitrobenzaldehydes have been reacted with two activated alkenes, methyl vinyl ketone (MVK) and methyl acrylate, under Baylis-Hillman conditions to afford α-methylene-β-hydroxylalkyl derivatives in moderate to excellent yields. The reactions were conducted using the tertiary amine catalysts, 1,4-diazabicyclo[2.2.2]octane(DABCO) or 3-hydroxyquinuclidine (3-HQ) with chloroform as solvent, and yields were optimised by varying the catalyst, reagent concentrations and the reaction time. Reductive cyclization of the Baylis-Hillman adducts via catalytic hydrogenation, using 10% palladiumon-carbon catalyst in ethanol, afforded quinoline and quinoline N-oxide derivatives. In some cases “acyclic” reduction products were also isolated. Reaction of the Baylis-Hillman MVK adducts with HCl, has resulted in effective nucleophilic (SN’) displacement of the hydroxyl group to afford allylic chloride derivatives. Direct substitution of these chloro derivatives by secondary or primary amines, followed by catalytic hydrogenation gave quinoline derivatives containing a 3-aminomethyl substituent. The Baylis-Hillman ester adducts obtained from reaction with methyl acrylate were treated directly with various amines to give diastereomeric conjugate addition products. Reactions with piperazine gave N,N’-disubstituted piperazine products. The piperidine derivatives have been dehydrated to give cinnamate esters in moderate yields. The products, which have all been satisfactorily characterised by elemental (HRMS) and spectroscopic (1- and 2-D NMR) analysis, constitute a “library” of compounds for in silico and in vitro studies as potential HIV integrase inhibitors.
- Full Text:
- «
- ‹
- 1
- ›
- »