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.
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- Date Issued: 2015
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
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- Date Issued: 2015
Nonlinear optical studies of phthalocyanines and triazatetrabenzcorroles in solution and in thin films
- Authors: Mkhize, Nhlakanipho Colin
- Date: 2015
- Subjects: Phthalocyanines , Thin films , Nonlinear optics , Phosphorus
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4542 , http://hdl.handle.net/10962/d1017922
- Description: This work presents photophysical and nonlinear optical properties of a novel Cd 2,3-[octakis{4-tert-butylphenoxyphthalocyanine}] (CdOtBPPc) and compared with those of Pb 2,3-[octakis{4-tert-butylphenoxyphthalocyanine}] (PbOtBPPc). For both the CdOtBPPc and PbOtBPPc, third order imaginary susceptibility and second order hyperpolarizability values were found to be within the limit set for good optical limiters. The Pcs were embedded in poly (methyl methacrylate) (PMMA) and poly(bisphenol A carbonate) (PBC) as thin films. The optical limiting values of the Pcs once embedded in film were found to be greatly improved and the limiting intensity of each film was well below the maximum threshold. Both PbOtBPPc and CdOtBPPc showed better optical limiting when embedded in PBC compared to PMMA. CdOtBPPc shows better nonlinear optical behaviour than PbOtBPPc in solution and as thin films, even though the former is aggregated in solution. Novel phosphorus triazatetrabenzcorroles (TBC) tetrasubstituted at the α- and β- and octa substituted at the β- positions of the peripheral fused benzene rings with t-butylphenoxy substituents were prepared and characterized. The effects of the substituents and the missing aza-nitrogen on the electronic structures and optical spectroscopy are investigated with TD-DFT calculations and MCD spectroscopy. The optical limiting properties were investigated to examine whether the lower symmetry that results from the direct pyrrole-pyrrole bond and hence the permanent dipole moment that is introduced result in higher safety thresholds, relative to the values that have been reported for phthalocyanines. The suitability of the compounds for singlet oxygen applications has also been examined. Novel phosphorus phthalocyanines, analogous to the triazatetrabenzcorroles were also investigated. Due to their high photodegradation quantum yield however, only the fluorescence quantum yields and lifetimes were able to be determined.
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- Date Issued: 2015
Photo-physicochemical studies and photodynamic therapy activity of indium and gallium phthalocyanines
- Authors: Tshangana, Charmaine Sesethu
- Date: 2015
- Subjects: Quantum dots , Nanoparticles , Photochemotherapy , Phthalocyanines
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4548 , http://hdl.handle.net/10962/d1017928
- Description: The potential toxicity of seven different types of quantum dots without shell (L-cysteine-CdTe, TGA-CdTe, MPA-CdTe, TGA-CdSe) and with the shell (GSH-CdSe@ZnS, GSH-CdTe@ZnS,) with different capping agents were evaluated. The growth inhibitory effects of the various quantum dots on human pancreatic BON cancerous cells were determined. The least cytotoxic of the various quantum dots synthesized and the one displaying the lowest growth inhibitory potential and no embryotoxicity was determined to be the GSH-CdSe@ZnS quantum dots. The GSH-CdSe@ZnS quantum dots were then conjugated to gallium, aluminium and indium octacarboxy phthalocyanine and the photophysical behaviour of the conjugates studied for potential use in photodynamic therapy and imaging applications. The sizes, morphology, thermal stability and confirmation of successful conjugation was determined using X-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR), respectively. The study was extended by conjugating amino functionalized magnetic nanoparticles (Fe₃O₄) to indium octacarboxy phthalocyanine to study the photophysical behaviour of the conjugate as a potential bi-functional anti-cancer agent (hyperthermia and photodynamic therapy applications). A three-in-one multifunctional nanocomposite comprising of the quantum dots, magnetic nanoparticles and indium octacarboxy phthalocyanine was developed with the aim of developing a multifunctional composite that is able detect, monitor and treat cancer. All conjugates showed improved and enhanced photophysical behaviour. Finally, GSH-CdSe@ZnS conjugated to aluminium octacarboxy phthalocyanine was applied in human pancreatic carcinoid BON cells. The conjugates induced cell death dose-dependently.
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- Date Issued: 2015
Photodynamic antimicrobial chemotherapy activities of porphyrin- and phthalocyanine-platinum nanoparticle conjugates
- Authors: Managa, Muthumuni Elizabeth
- Date: 2015
- Subjects: Photochemotherapy , Anti-infective agents , Porphyrins , Phthalocyanines , Platinum , Nanoparticles , Bioconjugates , Electrospinning
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4539 , http://hdl.handle.net/10962/d1017919
- Description: This work reports on the conjugation of differently shaped Pt nanoparticles (PtNPs) with ClGa(III) 5,10,15,20-tetrakis-(4-carboxyphenyl) porphyrin (1) as well as chloro - (5,10,15,20-tetrakis (4- (4- carboxy phenycarbonoimidoyl) phenyl) porphyrinato) gallium(III) (2) The work also reports on platination of dihydroxosilicon octacarboxyphthalocyanine (OH)₂SiOCPc (3) to give dihydroxosilicontris(diaquaplatinum)octacarboxyphthalocyanine (OH)₂SiOCPc(Pt)₃ (4). The resulting conjugates were used for photodynamic antimicrobial chemotherapy against S. aureus, E. coli and C. albicans. The degree of photo-inactivation is dependent on concentration of the conjugates, light dose (fluence) and illumination time. The log reduction obtained for 1 when conjugated to cubic PtNPs was 4.64 log (which indicate 99.99 percent of the bacteria have been killed), which is much higher than 3.94 log unit for 1-hexagonal PtNPs and 3.31 log units for 1-unshaped PtNPs. Complex 2 conjugated to hexagonal PtNPs showed 18 nm red shift in the Soret band when compared to 2 alone. Complex 2 and 2-hexagonal PtNPs as well showed promising photodynamic antimicrobial chemotherapy (PACT) activity against S. aureus, E. coli and C. albicans in solution where the log reduction obtained was 4.92, 3.76, and 3.95 respectively for 2-hexagonal PtNPs. The singlet oxygen quantum yields obtained were higher at 0.56 for 2-hexagonl PtNPs in DMF while that of 2 was 0.52 in the same solvent. This resulted in improved PACT activity for 2-hexagonal PtNPs compared to 2. Complex 4 showed slight blue shifting of the absorption spectrum when compared to complex 3 The antimicrobial activity of 4 were promising as the highest log reduction value was observed when compared to the porphyrin conjugates.
- Full Text:
- Date Issued: 2015
Structural studies on yeast eIF5A using biomolecular NMR and molecular dynamics
- Authors: Sigauke, Lester Takunda
- Date: 2015
- Subjects: Molecular dynamics , Reverse transcriptase , HIV (Viruses) , HIV infections , Eukaryotic cells , Yeast
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4547 , http://hdl.handle.net/10962/d1017927
- Description: Eukaryotic initiation factor 5A, eIF5A, is a ubiquitous eukaryotic protein that has been shown to influence the translation initiation of a specific subset of mRNAs. It is the only protein known to undergo hypusination in a two-step post translational modification process involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) enzymes. Hypusination has been shown to influence translation of HIV-1 and HTLV-1 nuclear export signals, while the involvement of active hypusinated eIF5A in induction of IRES mediated processes that initiate pro-apoptotic process have inspired studies into the manipulation of eIF5A in anti-cancer and anti-diabetic therapies. eIF5A oligomerisation in eukaryotic systems has been shown to be influenced by hypusination and the mechanism of dimerisation is RNA dependent. Nuclear magnetic resonance spectroscopy approaches were proposed to solve the structure of the hypusinated eIF5A in solution in order to understand the influence of hypusination on the monomeric arrangement which enhances dimerisation and activates the protein. Cleavage of the 18 kDa protein monomer by introduction of thrombin cleavage site within the flexible domain was thought to give rise to 10 kDa fragments accessible to a 600 MHz NMR spectrometer. Heteronuclear single quantum correlation experiments of the mutated isotopically labelled protein expressed in E. coli showed that the eIF5A protein with a thrombin cleavage insert, eIF5AThr (eIF5A subscript Thr), was unfolded. In silico investigations of the behaviour of eIF5A and eIF5AThr (eIF5A subscript Thr) models in solution using molecular dynamics showed that the mutated model had different solution dynamics to the native model. Chemical shift predictors were used to extract atomic resolution data of solution dynamics and the introduction of rigidity in the flexible loop region of eIF5A affected solution behaviour consistent with lack of in vivo function of eIF5AThr (eIF5A subscript Thr) in yeast. Residual dipolar coupling and T₁ relaxation times were calculated in anticipation of the extraction of experimental data from RDC and relaxation dispersion experiments based on HSQC measurable restraints.
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- Date Issued: 2015
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.
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- Date Issued: 2015