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.
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- Date Issued: 2010
Application of the Baylis-Hillman methodology in the construction of novel heterocyclic derivatives
- Authors: Nyoni, Dubekile
- Date: 2008
- Subjects: Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4402 , http://hdl.handle.net/10962/d1006704
- Description: Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values.
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- Date Issued: 2008
Studies directed towards the synthesis of chromone carbaldehyde-derived HIV-1 protease inhibitors
- Authors: Molefe, Duduzile Mabel
- Date: 2008
- Subjects: Protease Inhibitors , HIV infections , HIV (Viruses) , AIDS (Disease) , Proteolytic enzymes , Heterocyclic compounds -- Derivatives , Chemical kinetics , Nuclear magnetic resonance spectroscopy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4526 , http://hdl.handle.net/10962/d1015542
- Description: A series of chromone-3-carbaldehydes have been prepared using Vilsmeier-Haack methodology while a corresponding series of chromone-2-carbaldeydes have been synthesized via the Kostanecki-Robinson reaction. Baylis-Hillman reactions have been conducted on both series of chromone carbaldehydes using three different catalysts, viz., 1,4-diazabicyclo(2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) and 3-hydroxyquinuclidine (3HQ), and acrylonitrile, methyl acrylate and methyl vinyl ketone as the activated alkenes. These reactions have typically (but not always!) afforded both normal Baylis-Hillman and dimeric products. Attention has also been given to the use of 1-methyl-2-pyrrolidine (1-NMP), an ionic liquid, to replace normal organic solvents, and it has been found that, in the presence of DABCO, chromone-3-carbaldehydes afford the dimeric products alone. Reactions of chromone-3-carbaldehydes with methyl vinyl ketone have yielded unexpected, novel adducts, which appear to arise from preferential attack at C(2) in the chromone nucleus. Research on chromone-2-carbaldeydes under Baylis-Hillman conditions has also resulted in the formation of some interesting products instead of the expected Baylis-Hillman adducts. The Baylis-Hillman products have been explored as substrates for aza-Michael reactions using various amino derivatives including protected amino acids in the presence of the tetrabutylammonium bromide (TBAB) and the ionic liquid, 3-butyl-1- methylimidazoleboranetetrafluoride (BmimBF₄), as catalysts. The aza-Michael products have been targeted as truncated ritonavir analogues for investigation as potential HIV -1 protease inhibitors, and representative compounds have been subjected to enzyme inhibition assays to explore the extent and type of inhibition. Lineweaver-Burk and Dixon plots have indicated competitive inhibition in one case as well as non-competitive inhibition in another, and the inhibition constants (Ki) have been compared with that of the ritonavir. Computer modelling studies have also been conducted on selected chromonecontaining derivatives, using the ACCELRYS Cerius² platform. Interactive docking of the chromone-containing ligands into the HIV -1 protease receptor site, using the Ligandfit module, has indicated the importance of hydrogen-bonding interactions mediated by bridging water molecules situated in the receptor cavity. NMR spectroscopy has been used to elucidate complex and competing mechanistic pathways involved in the Baylis-Hillman reactions of selected 2-nitrobenzaldehydes with MVK in the presence of DABCO - reactions which afford the normal BaylisHillman product, the MVK dimer and syn- and anti-Baylis-Hillman type diadducts. The kinetic data confirm the concomitant operation of two pathways and reveal that, in the initial stage of the reaction, the product distribution is kinetically controlled, whereas in the latter stage, thermodynamic control results in the consumption of the normal Baylis-Hillman product and predominance of the anti-diadduct.
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- Date Issued: 2008
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.
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- 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
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- Date Issued: 2007
Application of the Baylis-Hillman reaction in the preparation of quinoline derivatives
- Authors: Pakade, Vusumzi Emmanuel
- Date: 2006 , 2013-06-11
- Subjects: Heterocyclic compounds -- Derivatives , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4442 , http://hdl.handle.net/10962/d1007669 , Heterocyclic compounds -- Derivatives , Quinoline
- Description: The reaction of various 2-nitrobenzaldehyde derivatives with methyl vinyl ketone (MVK) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) has afforded the Baylis-Hillman adducts in moderate to good yield. Dissolution of the catalyst in the solvent before the addition of the aldehyde was observed to improve the yield. Reduction of the Baylis-Hillman adducts was effected by catalytic hydrogenation using a 10% palladium-on- carbon catalyst in ethanol to give quinoline and quinoline-N-oxide derivatives and, in some cases, acyclic reduction products. All products were characterised using NMR and, where appropriate, HRMS methods. Selected quinoline-N-oxides were successfully converted to their corresponding quinoline derivatives using phosphorus tribromide (PBr₃) and DMF as solvent. Conjugate addition of the benzylamine and piperidine nucleophiles to the Baylis-Hillman adducts was also investigated but proved problematic, with one of the substrates undergoing a retro-Baylis-Hillman reaction to afford the aldehyde in ca. 40% yield, but seemingly only traces of the required product. Perkin-type coupling of two 2-methylquinolines with benzaldehyde was successfully effected to afford the desired styrylquinoline derivatives confirming the potential of the Baylis-Hillman approach to the construction of the analogues of known HIV-1 integrase inhibitors. Three ¹³C NMR chemical shift prediction programmes, viz., Chem Window, neural network and HOSE (hierarchically ordered spherical description of environment) methods were applied to selected representative compounds prepared in the project. The results from the three programmes correlated reasonably well with the experimental carbon-13 chemical shift data for each of the selected compounds.
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- Date Issued: 2006
Applications of Baylis-Idllman methodology in the synthesis of chromene derivatives
- Authors: Nocanda, Xolani Wittleton
- Date: 2001
- Subjects: Heterocyclic chemistry , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4556 , http://hdl.handle.net/10962/d1018257
- Description: The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
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- Date Issued: 2001