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1
MacDonald, Ranald John. "Novel routes to heterocyclic Azo compounds." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5787.
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The potential use of electron-deficient heterocyclic azo compounds as inkjet dyes was explored. 2-Nitrosopyridine could be used to form a series of azo compounds via the Mills’ reaction with electron-rich aromatic amines. Conditions for this process were optimised by varying solvent and pH. In the presence of ethers, 2-nitrosopyridine is quickly reduced to azoxypyridine. This reaction follows first order kinetics; diethyl and diisopropyl ether react at similar rates, whereas cyclic ethers such as THF are far slower. Organic bases such as Hunigs base were also found to promote formation of azoxypyridine. The mechanism of this reduction was studied. The electrochemistry of 2-nitrosopyridine and azoxypyridine was also explored. Using the optimised conditions for the Mills’ reaction, 2-nitrosopyridine not only reacts with electron-rich amines but also electron-deficient examples. The series was also expanded to include other heterocycles as well as pyridine via the corresponding heterocyclic nitroso compound. Other nitroso compounds prepared were 1- nitrosoisoquinoline, 2-nitrosopyrazine, 4-nitrosopyrimidine and 2-nitrosopyrimidine. The absorption maxima of azo compounds prepared from these precursors were found to correlate with the values for the corresponding azobenzenes. 2-Nitrosopyridine and 2-nitrosopyrimidine react with diamines to give monoazo products. These in turn could be diazotised and coupled with various components to give either bisazo or trisazo compounds. These dyes were tested for their ozone and light fastness properties. The bisazo examples were found to have good ozone fastness but poor light fastness. The pyrimidine examples only showed a slight improvement in ozone and light fastness compared to their pyridine analogue. 2,3-Phthalocyanines are important components in cyan dyes. New routes to precursors of these compounds were explored using flash vacuum pyrolysis (FVP).
2
Emans, John. "Synthesis of novel heterocyclic polymers." Thesis, University of St Andrews, 1987. http://hdl.handle.net/10023/15299.
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This work details the synthesis, characterisation and fabrication of a range of copolyesters, containing various angular disrupters, especially disubstituted 2,5-diphenyl- -1,3,4-oxadiazoles. These disrupters were incorporated into the polymers, to reduce the temperature at which the polymers may be processed, to enable their fabrication into fibres. The majority of the polymers prepared were found to be liquid crystalline. However, if the angular disrupter content of the polymer was high, it was found that the resultant polymers were non-liquid crystalline. The polymers were prepared by a melt acidolysis process carried out under a nitrogen flow and subsequently under vacuum, as described in Chapter 3. Eighteen of the polymers were characterised in some detail, though a measure of the relative molecular weights was thought to be of little importance in this work, since all polymers were of a different composition. Differential scanning calorimetry and hot-stage microscopy revealed that several of the polymers had rather unusual melting behaviour. The eighteen polymers that were closely characterised were spun into fibres, using a small melt-spinning apparatus that was designed and produced by Bradford University Research Ltd, The resultant fibres were characterised by differential scanning calorimetry, X-ray diffraction end tensile testing. The general conclusion of the work is that although a reduction in the processing temperature of the polymer is achieved by the incorporation of angular disruptors, which is advantageous, the tensile strength and thermal stability of the fibres produced from such polymers are reduced.
3
Nyoni, Dubekile. "Application of the Baylis-Hillman methodology in the construction of novel heterocyclic derivatives." Thesis, Rhodes University, 2008. http://eprints.ru.ac.za/1134/.
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Philbin, Simon Patrick. "Studies of novel nitro-substituted nitrogen heterocyclic compounds." Thesis, Brunel University, 2001. http://bura.brunel.ac.uk/handle/2438/2165.
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The novel candidate high energy insensitive explosive; 2,5-diamino-3,6-dinitropyrazine (ANPZ-i) has been prepared in acceptable overall yield. ANPZ-i was synthesised by the nitration of 2,5-diethoxypyrazine using nitronium tetrafluoroborate (NO2+BF4-) in sulfolane and the subsequent amination of 2,5-diethoxy-3,6-dinitropyrazine, under autoclave conditions. Oxidation studies towards the dioxide derivative of ANPZ-i, 2,5-diamino-3,6-dinitropyrazine-1,4-dioxide (PZDO), were unsuccessful. The synthesis of existing high explosives; 2,6-diamino-3,5-dintropyrazine (ANPZ) and 2,6-diamino-3,5-dinitropyrazine-1-oxide (PZO) has been scaled up to produce approximately 25 g batches of material. A number of novel nitrations using NO2+BF4- have been carried out on a range of chloro-, methyl- and hydroxy-functionalised quinoxalines and quinazolines. A range of novel functionalisations have also been carried out on the platform molecule; 2,4-diamino-6,8-dinitroquinazoline giving rise to 2,4-diamino-6,8-dinitroquinazoline-1,3-dioxide (di-N-oxidation product), 2,4,7-triamino-6,8-dinitroquinazoline (monoamination product) and 2,4,6,8-tetra-aminoquinazoline (dihydrogenation product). Detonics molecular modelling was carried out on the following target molecules: 2,5-diamino-3,6-dinitropyrazine-1,4-dioxide (PZDO), 2,5,8-triamino-3,6,7-trinitroquinoxaline-1-oxide and 2,5,7-triamino-4,6,8-trinitroquinazoline-1-oxide. The detonation velocity of the new explosive molecule; 2,5-diamino-3,6-dinitropyrazine (ANPZ-i) was calculated and it was found to be a similar value to that obtained experimentally for the existing high explosive RDX. Calculation by molecular modelling of the steric energies of ANPZ, PZO, ANPZ-i and PZDO gave a quantitative assessment of the difficulty in oxidising ANPZ-i to give PZDO. Extensive analysis of carbon-13 NMR spectroscopy shift values was carried out for approximately twenty nitrogen heterocyclic compounds. Comparison of shift values indicated consistency in the interpretations. On-line literature searches have shown that the following compounds prepared in this project are new: 2,3,6-trichloro-5-nitroquinoxaline, 2,3-dimethoxy-6,7-dinitroquinoxaline, 2,3,6-trichloroquinoxaline-1-oxide, 2,4-diamino-6,8-dinitroquinazoline-1,3-dioxide, 2,4,7-triamino-6,8-dinitroquinazoline and 2,5-diamino-3,6-dinitropyrazine (ANPZ-i). Furthermore, new synthetic routes have been used in the preparation of the following compounds: 2,3-dichloro-5-nitroquinoxaline, 2,3,6,7-tetrachloro-5-nitroquinoxaline, 2-hydroxy-6-nitroquinoxaline, 2-hydroxy-3-methyl-6-nitroquinoxaline and 2,5-diethoxy-3,6-dinitropyrazine.
5
Al-Suwaidan, I. A. "Heterocyclic compounds as novel substrates for glutathione transferase." Thesis, University of Bradford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378114.
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Taher, Abutariq. "Novel cyclisations of nitro-compounds for heterocyclic synthesis." Thesis, Loughborough University, 2001. https://dspace.lboro.ac.uk/2134/34705.
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The research described in this thesis is aimed at developing novel methods of synthesis for heterocyclic compounds, in particular cyclisation reactions involving the nitro functional group. The first chapter describes investigations into the Wallach imidazole synthesis. A number of chloroimidazoles were prepared, but the possible extension to highly functionalised imidazoles proved elusive. The second chapter describes studies on the successful conversion of nitroimidazolyl malonates 1 into imidazo[4,5-c]isoxazoles 2, Scheme 1. Related cyclisations are described in chapter three and the thiophene fused isoxazole 3 was successfully prepared. Chapter four investigates the reactivity of the strained imidazo[4,5-c]isoxazole heterocycles. Ring opening of the isoxazole occurred on reaction with phosphines to give iminophosphorane derivatives. Reactions with electron deficient acetylenes led to pyrrolyl imidazoles 4, and a novel [1,4]diazepino[2,3-c]isoxazole 5, Scheme 1, but no reaction was observed with alkenes. [Illustration omitted.] Chapter five entails synthesis of a series of 5-aryl-2H,1H-imidazo[4,5-d][1,2,3]triazole derivatives 7. Triethyl N-1-ethyl-2-methyl-4-nitro-1H-imidazol-5-yl phosphoramidate compound 6 was treated with a range of aryl isocyanates which gave imidazo[4,5-c]triazoles 7 in moderate to good yields. A mechanism involving carbodiimide formation was postulated and was supported using infra-red spectroscopy, Scheme 2. Chapter six reports a new synthesis of 5-aryl-2H indazole derivatives 9 by base catalysed reaction of 2-nitrobenzyl triphenylphosphonium bromide salts 8 with a range of aryl isocyanates. A mechanism of this reaction was proposed and investigated by infra-red spectroscopy, Scheme 3.
7
Killoran, P. M. "Development of novel heterocyclic compounds as vascular targeting agents." Thesis, University of Salford, 2015. http://usir.salford.ac.uk/36856/.
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In chapter one the biology of cancer is introduced along with a brief history of drug treatment and the status quo of cancer therapeutics. This includes a general overview of cancer prevalence, carcinogenesis, and biochemistry. The main targets for cancer therapeutics are introduced along with in-depth look at cancer vasculature, tubulin binding agents and their mechanisms of action. In chapter two the development of the routes to the dibenzo[c,e]oxepine target compounds are described. The optimisation of a key biaryl precursor molecule for these analogues is described. This includes a brief overview of palladium catalysed coupling chemistry and a screen for suitable catalytic systems. In chapter three the development of an intramolecular ring closing process for dibenzo[b,d]oxepine is described. This includes investigation into non-phenolic oxidative coupling and a screen for oxidants. Palladium/phosphine catalysed intramolecular arylation is also discussed. In chapter four the synthesis of the target compounds is described along the development of routes to further analogues. In chapter five the biological testing of compounds is discussed. This features an introduction to biological evaluation methods for anti cancer compounds. The results for all of the MTT and tubulin binding assays (MA) are presented, revealing a fluorinated dibenzo[c,e]oxepine analogue with cytotoxicity within the nanomolar range (MTT K562 - IC50 60 nm, MA - 1.2 µM). Furthermore a link has also been established between the cytotoxic activity profiles of a series of simple biaryl compounds and Combretastatin A-4.
8
Iannarelli, Paul M. "Routes to novel azo compounds." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/3492.
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Routes to novel heterocyclic azo compounds and components of use as potential inkjet dyes were investigated. A new route to fluorenones from biphenyl acid chlorides using FVP (Flash Vacuum Pyrolysis) has been discovered. Fluorenone and 4-methylfluoren-9-one were prepared by FVP of 2-phenylbenzoyl chloride and 2-methylbiphenyl-2-carbonyl chloride respectively. Xanthen-9-one and thioxanthen-9-one were also prepared by FVP from the corresponding acid chlorides. 9-Phenanthrol could also be prepared via the FVP of biphenylacetyl choride and the application of this method to a heterocylic thiophene system afforded naphtho[1,2-b]thiophen-4-ol. Naphtho[2,1-b]thiophen-4-ol and naphtho[1,2-b]furan- 4-ol could be obtained in low yields by the FVP of (2-thiophen-3-ylphenyl)acetic acid methyl ester and (2-furan-2-ylphenyl) acetic acid methyl ester over a tungsten trioxide catalyst. Coupling of these systems with the diazonium salt of Acid Yellow 9 afforded the corresponding azo compounds. New heterocyclic dyes were also prepared from the condensation of heterocyclic hydrazines with 4,9-disulfophenanthrenequinone. Pyridine, pyridazine, phthalazine, isoquinoline and 2-quinoline disulfophenanthrene quinone metallised 2:1 nickel complexed magenta dyes were prepared. Industrial tests by standard methods revealed the pyridazine dye has a particularly impressive balance of light and ozone fastness over similar magenta dyes. The reaction of an arylnitro compound with 2-aminopyridine appeared to be an attractive and high yielding route to 2-(phenylazo)pyridine. However, application of this reaction to substituted and naphthalene systems failed. This afforded byproducts due to nucleophilic substitution of groups such as methoxy and the relatively uncommon nucleophilic substitution of hydrogen with none of the required azo products obtained. Therefore it appeared that the reaction of a nitro and amine was not a robust and versatile route to heterocyclic azo compounds. An alternate route to heterocyclic azo compounds involved the use of the Mills reaction by the condensation o-anisidine, p-chloroaniline, 2-aminophenol, 3- aminophenol, naphthylamine, 8-amnioquinoline and 2-acetylamino-5-aminobenzenesulfonic acid with 2-nitrosopyridine afforded the heterocyclic azo products in moderate to high yields. The Mills reaction does appear to be the favored route to heterocyclic azo compounds. Several factors were identified which affect the process of bisazo coupling of chromotropic acid and products obtained. Reaction at the ipso position of monoPACAs (2-phenylazochromotropic acid) leading to increased yields of the ipso substitution monoPACA by-product as opposed to the expected bisazo coupling position was a major problem. Studies indicated reactivity at the ipso position was greatly reduced by the presence of electron withdrawing groups around the phenyl ring of the monoPACA. Further study indicated reaction at the bisazo coupling position increased with the strength of the diazonium salt used in bisazo coupling. Therefore the electronic nature of the monoPACA starting material and the diazonium salt used in bisazo coupling greatly affected the products obtained. Reaction pH studies also revealed attack at the bisazo coupling position increases with pH and at lower pH (5.0 – 8.0) attack at the ipso position dominated. Reactivity of the monoPACA starting material also increased with pH. The influence of steric effects upon bisazo coupling revealed, in the cases where ortho sulfonic acid groups were present in the monoPACA, a reduction in attack at the ipso position. Hence the reaction appeared to be directed towards the required bisazo coupling position.
9
Rogers, James William. "1-benzotriazolyl-2-propynones as novel 1,3-biselectrophiles, benzotriazole-assisted thioacylation and synthesis of energetic materials." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0013389.
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10
Grisle, Roger Anthony. "Synthesis of novel heterocyclic difluoro monomers via the chemistry of reissert compounds." Thesis, This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-05042010-020216/.
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Ella-Menye, Jean-Rene. "Synthesis of Novel Chiral Heterocyclic Compounds for Antibacterial Agents and Peptidomimetics." ScholarWorks@UNO, 2007. http://scholarworks.uno.edu/td/611.
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Small chiral molecules are very important building blocks in the synthesis of biologically active compounds. These building blocks include nitrogen and oxygen-containing heterocycles such as 2-oxazolidinones, 1,3-oxazinan-2-ones, 2-oxazolines, oxazines, morpholine and morpholinones. Because of their interesting properties, chiral heterocycles have stirred great interest in the synthetic chemist community to develop useful and efficient strategies to these molecules. In this dissertation, the design and syntheses of various heterocyclic building blocks are presented, as well as the testing of their biological activities as antibacterial. Another very interesting family of heterocycle-containing molecules are the Aeruginosins. They are a family of marine natural products isolated from a blue-green algae, which display inhibitory activity against serine proteases such as thrombin, trypsin, and factor VIIa. Most aeruginosins contain an heterocyclic moiety called the 2-carboxy-6-hydroxyoctahydroindole (Choi) ring; this Choi moiety is a rigid bicyclic unnatural amino acid and is the core structure in the aeruginosins, indispensable to their biological activity. A synthesis of a ring-oxygenated variant of the Choi from D-mannose is reported in this dissertation. The ring-oxygenated variant of 2-carboxy-6-hydroxyoctahydroindole can potentially be used as a surrogate of Choi in the design and synthesis of aeruginosin-based thrombin inhibitors.
12
Guilani, Bardia. "Synthesis of novel heterocyclic polymers via the chemistry of Reissert compounds." Thesis, Virginia Tech, 1990. http://hdl.handle.net/10919/42072.
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The chemistry of a well established class of compounds, known as Reissert compounds, was used to prepare several novel N-heterocyclic polymers. Initially, alkylation of quinoline Reissert compounds was closely examined to test the feasibility of the use of such compounds as difunctional monomers. An A-B and an A-A monomer were then prepared by the reaction of quinoline with p-formylbenzoyl chloride and isophthaloyl chloride, respectively. The former monomer could be polymerized interfacially to afford a low molecular weight polyester exhibiting Tg of 190°C.
Several novel bis-isoquinolines were prepared using an en amine reaction reported by Minter and Re.52 One of these bis-isoquinolines was used to prepare two novel bis-Reissert compounds which could be polymerized with several dialdehydes to obtain high molecular weight N-heterocyclic polyesters. Cleavage of the ester groups afforded a novel N-heterocyclic polyalcohol. It was observed that circumvention of a rearrangement reaction particular to Reissert compounds by molecular design led to the synthesis of N-heterocyclic polyesters that had the highest molecular weights and intrinsic viscosities.
A novel N-heterocyclic difluorodiketone was prepared in four steps using the enamine reaction of Minter and Re52 and Reissert compound chemistry. The diketone was polymerized via standard techniques 72 to afford several novel poly(N-heteroaryl-ether-ketones) with high glass transition temperatures and thermal stabilities. Thus, polymerization of 1,4-bis(4-fluorobenzoyl)isoquinoline with biphenol yielded a poly(ether-ketone) with an intrinsic viscosity of 0.34 dl/g. This polymer showed Tg at 209°C and was stable up to 500°C in air.
Master of Science
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陳淑妤 and Suk-yu Florence Chan. "Novel synthesis and chemistry of 1, 4, 2-dithiazolium salts." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1988. http://hub.hku.hk/bib/B30426352.
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Yar, Muhammad. "Applications of Vinyl Sulfonium Salts in a Novel Synthesis of Heterocyclic Compounds." Thesis, University of Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520190.
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Shawcross, Andrew Paul. "The synthesis of novel heterocyclic compounds and observations on the Vilsmeier reaction." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328112.
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McFadden, Helen Georgina, and n/a. "Synthesis and herbicidal properties of some pyrazole and pyrimidine heteocycles." University of Canberra. Biomedical Sciences, 1992. http://erl.canberra.edu.au./public/adt-AUC20060918.160845.
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Four main series of novel heterocyclic compounds were successfully syniliesised.
Two of these series were found to be post-emergence herbicides with the activities of each
being based on a different mode of action. The (pyrazole-4-yl)alkanones are inhibitors of
protoporphyrinogen oxidase, an enzyme in chlorophyll biosynthesis, whereas alkyl 3-arylsulfonylamino-
3-methyllhio-2-(pyrimidin-2-ylcarbamoyl)acrylates and pyrimidin-2-yl 3-(2-
chlorophenyl)sulfonyl-amino-3-methylthio-2-cyanoacrylamides (collectively termed
"vinylogous sulfonylureas") are inhibitors of acetohydroxy acid synthase (AHAS). an enzyme
in branched-chain amino acid biosynthesis. Both these enzymes are established targets
for current commercial herbicides.
Studies of the utility of 2-(l-ethoxyalkylidene)-3-oxoaIkanenitriles (acrylonilriles)
in heterocycle synthesis were facilitated by the recent development of a convenient route
to these starting materials. Acrytonitriles were reacted with different hydrazines to give
(pyrazol-4-yl)alkanones and pyrazole-4-carbonitriles in varying proportions depending on
the reaction conditions and the substituents on the reactants. Although distinction between
alternative 3- and 5-substituted pyrazoles is a perennial problem in pyrazole synthesis, in
this case the products of these reactions were successfully characterised and identified using
a range of n.m.r. spectroscopy techniques. Once the herbicidal mode of action of the
(pyrazol-4-yl)alkanones had been confirmed, synthesis of a series of analogues allowed the
structural elements contributing to biological activity to be identified. The reaction of
acrylonitriles with bidetate nucleophiles such as thiourea gave novel pyrimidines. but these
compounds were not herbicidal.
The vinylogous sulfonylureas were synthesised using established procedures to
obtain novel compounds structurally related to the commercial herbicide chlorsulfuron. The
biological activity of the vinylogous sulfonylureas was found to be sensitive to apparently
minor changes in structure, but x-ray crystallographically-generated structures of an active
and an inactive member of the series revealed marked differences in conformation. Some
of the vinylogous sulfonylureas were used as synthons for pyrazole and pyrazolopyrimidine
derivatives. Although these compounds did not exhibit herbicidal activity, this synthesis
provided the basis for some interesting chemistry. Unexpected elimination of the arylsulfonylamino
group was observed when a vinylogous sulfonyurea was treated with methyl
hydrazine. In order to confirm the identity of the 3-methylthiopyrazole product, model compounds
were synthesised using alternative routes. The resulting pairs of 3- and 5-substituted
pyrazoles were characterised using n.m.r spectroscopy.
17
Fischer, Kristapher Edward, and University of Lethbridge Faculty of Arts and Science. "Synthesis and characterization of novel cyclophanes from 5,5'-bi(isobenzofuran)." Thesis, Lethbridge, Alta. : University of Lethbridge, Faculty of Arts and Science, 2005, 2005. http://hdl.handle.net/10133/255.
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Isobenzofuran has since its discovery proven an important intermediate in the synthesis of novel organic compounds, due to its high reactivity in Diels-Alder reactions. This thesis details the synthesis, purification and characterization of cyclophane compounds derived from a novel analogue of isobenzofuran, 5,5'-bi(isobenzofuran). Because of the relative rarity of molecules containing multiple isobenzofuran units, 5.5'-bi(isobenzofuran) is an excellent candidate for study. Prelminary analysis of an additional novel analogue of isobenzofuran, 5.5'-bis(isobenzofuranyl) acetylene, is also presented.x, 119 leaves : ill. ; 29 cm.
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Rose, Nathan Rolf. "Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease." Thesis, Rhodes University, 2007. http://hdl.handle.net/10962/d1007220.
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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
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Rashamuse, Thompho Jason. "Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors." Thesis, Rhodes University, 2008. http://eprints.ru.ac.za/1332/.
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Hodson, Luke. "The synthesis of novel kinase inhibitors using click chemistry." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86704.
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Thesis (MSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Cancer is the leading cause of death on the planet, killing an estimated 8.2 million people in the year of 2012.The disease is associated with two families of genes, namely oncogenes and tumour suppressor genes. The hallmarks of cancer pathogenesis include gene amplification, point mutations or chromosomal rearrangements within these genes. Kinases are responsible for the reversible phosphorylation of proteins, which plays a significant and extensive role in cellular signal transduction. Aberrant kinase activity provokes overexpression, mutations and chromosomal translocation and results in the onset of onco- and tumorogenesis, ultimately leading to cancer. Inactivation of this class of enzyme is thus critical as it would result in the suppression of these unwanted activities. For this, researchers have developed kinase inhibitors, specifically targeting these proteins and thus inhibiting signal transduction pathways and tumour growth. This has resulted in great successes, particularly in the case of the commercial inhibitor, imatinib. However, resistance to approved therapeutic agents through mutations has resulted in the search for more potent and selective inhibitors to overcome these obstacles. This project involved the synthesis of bioactive heterocycles linked to 1,2,3-triazoles using either a C-C or C-N bond forming strategy. The synthetic methodology followed included the use of Sonogashira coupling reactions between3-bromoquinoline, 7-chloro-4-iodoquinoline, 4-bromoisoquinolineand5-bromoisoquinolineand trimethylsilylacetylene (TMSA), followed by deprotection of the TMS group to yield heterocycles bearing terminal alkynes. The synthesis of both benzyl azide and 2-(azidomethyl)pyridine as azide fragments, allowed for subsequent coupling of the synthesized azide and alkyne fragments through copper-mediated click chemistry, affording a library of 1,4-substituted 1,2,3-triazole based reversible kinase inhibitors. Synthesis of a second library of o-, m- and p-substituted nitro benzyl azides, allowed for both copper- and ruthenium-mediated click reactions, between the alkynes and nitro benzyl azides synthesized, to yield 1,4- and 1,5-substituted 1,2,3-triazoles, respectively. Finally, reduction of the incorporated o-, m- and p- substituted nitro group, and acylation of the resultant amine with acryloyl chloride, resulted in the incorporation of the important Michael acceptor moiety required for irreversible inhibition. This afforded a library of both reversible and potential irreversible triazole-based kinase inhibitors through efficient copper- and ruthenium-mediated click chemistry. Biological screening and activity assays against the wildtype, and two mutated forms of the EGFR kinase, were undertaken with these synthesized compounds.A number of synthesized inhibitors showed good selectivity for the mutated forms of the EGFR kinase only.The most potent inhibitor N-{2-{[4-(isoquinolin-4-yl)-1H-1,2,3-triazol-1-yl]methyl}phenyl}acrylamide,displayed efficacy in the low μM range - comparable to that of the FDA approved drug, gefitinib. The synthetic methodology derived in this project could be applied to the use of biological space probes with further investigatory research. Furthermore, from the biological screening results obtained, and the selectivity profile shown by these inhibitors, the synthesis of a second generation library of compounds is an additional research possibility.
AFRIKAANSE OPSOMMING: Kanker is die hoof oorsaak van sterftes ter wêreld, wat verantwoordelik is vir die dood van ongeveer 8.2 miljoen mense in die jaar 2012. Die siekte word geassosieer met twee geenfamilies, naamlik onkogene en gewasonderdrukkingsgene. Die kenmerke van kanker pathiogene behels geenversterking, puntmutasies of chromosomale herrangskikking binne in die gene. Kinase is verantwoordelik vir die omkeerbare fosforilering van proteine wat 'n uiters belangrike rol in sellulere sein transduksie speel. Abnormale kinase aktiwiteit lei tot ooruitdrukking, mutasies en chromosomale translokasie wat tot die ontwikkeling van onko- en gewasgroei en wat eindelik tot kanker lei. Deaktivering van die klas van ensieme is dus krities want dit sal die ongewenste abnormale aktiwiteite onderdruk. As gevolg van die bogenoemde, het navorsers kinase inhibeerders ontwikkel wat die spesifieke protein teiken en hiermee die sein transduksie roete asook gewas groei inhibeer. Hiermee het die sukses van inhibeerders veral die kommersiele inhibeerder, imatinib, grootliks toegeneem. Oor die afgelope jare het die belangstelling in die ontwikkeling van meer selektiewe en kragtige inhibeerders toegeneem as gevolg van die weerstand wat goedgekeurde terapeutiese middels opbou. In hierdie projek is daar gebruik gemaak van 'n C-C of C-N bindingsvorming strategie om bioaktiewe heterosikliese molekules te sintetiseer wat gekoppel is aan 1,2,3-triasool funksionele groepe. Die sintetiese metode maak gebruik van Sonogashira reaksies vir die 3-bromo-kwinolien, 7-chloro-4-iodokwinolien, 4-bromoisokwinolien en 5-bromoisokwinolien met trimetielsilielasetileen (TMSA), gevolg met die ontskerming van die TMS-groep om die terminale alkyn op die heterosiklusse te ontbloot. Die asied fragmente, bensiel asied en 2-(asidometiel)piridien, was toe gesintetiseer om met die gevormde heterosiklus alkyne 'n koper ondersteunende kliek chemie te ondergaan. 'n Reeks van 1,4-digesubstitueerde 1,2,3-triasool gebaseerde omkeerbare kinase inhibitore is toe gevorm. 'n Tweede reeks met o-, m-, en p- gesubtitueerde nitro bensiel asiede was gesintetiseer om 1,4- en 1,5- digesubtitueerde 1,2,3-triasole te sintetiseer met behulp van koper- en ruthenium ondersteunende kliek chemie. Laastens was die o-, m-, en p- nitro groepe gereduseer om 'n primêre amien te vorm. Die gevormende amien het 'n asileringsreaksie met akriloïel chloried ondergaan om die kern, die Michael akseptor, te inkorporeer. Die Michael akseptor word benodig om 'n onomkeerbare inhibitoriese aktiwiteit te kan uitvoer. Die projek het dus met behulp van kliek chemie, twee 1,2,3-triasool reekse gelewer wat omkeerbare en onomkeerbare inhibitoriese aktiwiteit kan uitvoer. Die verbindings gesintetiseerd in hierdie projek het keuringstoetse ondergaan teen die wilde tipe en teen twee gemuteerde forme van die EGFR kinase ensiem. Van hierdie verbindings het goeie selektiwiteit vertoon teenoor die gemuteerde EGFR kinase ensiem. Die mees aktiewe inhibeerder, N-{2-{[4-isokwinolin-4-iel)-1H-1,2,3-triasool-1-iel]feniel}akrielamied, het aktiwiteit in die lae μM reeks vertoon. Dié inhibisie waarde is vergelykbaar met die FDA goedgekeurde medikasie, gefitinib. In hierdie projek is sintetiese metodes ontwikkel wat toegepas kan word op meer intensiewe biologiese ondersoeke en asook meer navorsing. Die resultate vekry van die biologiese aktiwiteit, asook die verbindings se selektiwiteit, gee die moontlikheid vir die ontwikkeling en sintese van 'n tweede generasie verbindings.
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Sigauke, Lester Takunda. "An in-silico investigation of Morita-Baylis-Hillman accessible heterocyclic analogues for applications as novel HIV-1 C protease inhibitors." Thesis, Rhodes University, 2015. http://hdl.handle.net/10962/d1017913.
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Cheminformatic approaches have been employed to optimize the bis-coumarin scaffold identified by Onywera et al. (2012) as a potential hit against the protease HIV-1 protein. The Open Babel library of commands was used to access functions that were incorporated into a markov chain recursive program that generated 17750 analogues of the bis-coumarin scaffold. The Morita-Baylis-Hillman accessible heterocycles were used to introduce structural diversity within the virtual library. In silico high through-put virtual screening using AutoDock Vina was used to rapidly screen the virtual library ligand set against 61 protease models built by Onywera et al. (2012). CheS-Mapper computed a principle component analysis of the compounds based on 13 selected chemical descriptors. The compounds were plotted against the principle component analysis within a 3 dimensional chemical space in order to inspect the diversity of the virtual library. The physicochemical properties and binding affinities were used to identify the top 3 performing ligands. ACPYPE was used to inspect the constitutional properties and eliminated virtual compounds that possessed open valences. Chromene based ligand 805 and ligand 6610 were selected as the lead candidates from the high-throughput virtual screening procedure we employed. Molecular dynamic simulations of the lead candidates performed for 5 ns allowed the stability of the ligand protein complexes with protease model 305152. The free energy of binding of the leads with protease model 305152 was computed over the first 50 ps of simulation using the molecular mechanics Poisson-Boltzmann method. Analysis structural features and energy profiles from molecular dynamic simulations of the protein–ligand complexes indicated that although ligand 805 had a weaker binding affinity in terms of docking, it outperformed ligand 6610 in terms of complex stability and free energy of binding. Medicinal chemistry approaches will be used to optimize the lead candidates before their analogues will be synthesized and assayed for in vivo protease activity.
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Tukulula, Matshawandile. "The design and synthesis of novel HIV-1 protease inhibitors." Thesis, Rhodes University, 2009. http://eprints.ru.ac.za/1563/.
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Dulla, Balakrishna [Verfasser], and Oliver [Akademischer Betreuer] Reiser. "Synthesis and pharmacological characterization of novel N & O containing heterocyclic compounds as potential therapeutic agents / Balakrishna Dulla. Betreuer: Oliver Reiser." Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/1059003708/34.
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Lee, Yi-Chen. "Studies towards the development of novel HIV-1 integrase inhibitors." Thesis, Rhodes University, 2010. http://hdl.handle.net/10962/d1005022.
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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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Sherwood, Alexander M. "Design, Synthesis and Biological Evaluation of Novel Compounds with CNS-Activity Targeting Cannabinoid and Biogenic Amine Receptors." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1831.
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This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function.
The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry.
As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core.
A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.
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Wazeerud-Din, Idris. "Synthetic Approaches towards Novel Isoform Selective PI3K Inhibitors and Their Biological Activities against Prostate Cancer Cells." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/143.
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The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes. Novel PEG-IMP development, involved the synthesis of ethylene glycol tethered benzaldehydes and IMPs using traditional Williamson etherification synthesis, which afforded products at a high yield of 92-95%. We have then shown IMP and rIMP roles in its antiproliferative property towards PCa cells, specificity in inhibiting PI3K isoforms, and structural motif’s interaction with different residues in the kinase binding domain of the class I PI3K isoforms. The antiproliferative property towards PC3 cells shows increased activity with compounds containing pyridyl group on carbon 3 of the imidazo[1,5-a]pyridine parent moiety with signs of toxicity to PC3 within 24 hours of incubation and at 1 μM of the parent compound. Furthermore, the IMPs were tested against five prostate cellular lines: PC3, RWPE1, D145, LNCaP and LNCaP C81. IMPs showed little activity towards RWPE1 and increased activity towards PC3 cells. We determined that functionalizing the phenyl group at position 1 increased the efficacy of rIMP compared to the IMP. After showing increased toxicity to PC3 cells, it was important to investigate the mechanism in which IMP pose toxicity towards PC3 cells. The biochemical assay showed that rIMP was more effective in inhibiting PI3Kα isoform compared to both pan inhibitor wortmannin and IMP. Both IMP and rIMP inhibited more than 60% of PI3Kγ isoform activity at nanomolar concentrations. After showing IMPs affinity to PI3K isoforms, we investigated the binding interactions rIMP and IMP towards the PI3K isoforms using MOE molecular modeling software.
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Rayala, Ramanjaneyulu. "Design and Synthesis of Novel Nucleoside Analogues: Oxidative and Reductive Approaches toward Synthesis of 2'-Fluoro Pyrimidine Nucleosides." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2172.
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Fluorinated nucleosides, especially the analogues with fluorine atom(s) in the ribose ring, have been known to exert potent biological activities. The first part of this dissertation was aimed at developing oxidative desulfurization-fluorination and reductive desulfonylation-fluorination methodologies toward the synthesis of 2'-mono and/or 2',2'-difluoro pyrimidine nucleosides from the corresponding 2'-arylthiopyrimidine precursors. Novel oxidative desulfurization-difluorination methodology was developed for the synthesis of α,α-difluorinted esters from the corresponding α-arylthio esters, wherein the arylthio group is present on a secondary internal carbon. For the reductive desulfonylation studies, cyclic voltammetry was utilized to measure the reduction potentials at which the sulfone moiety of substrates can be cleaved.
The 5-bromo pyrimidine nucleosides and 8-bromo purine nucleosides act as crucial intermediates in various synthetic transformations. The second part of the present dissertation was designed to develop a novel bromination methodology using 1,3-dibromo-5,5-dimethylhydantoin (DBH). Various protected and deprotected pyrimidine and purine nucleosides were converted to their respective C5 and C8 brominated counterparts using DBH. The effect of Lewis acids, solvents, and temperature on the efficiency of bromination was studied. Also, N-bromosuccinimide (NBS) or DBH offered a convenient access to 8-bromotoyocamycin and 8-bromosangivamycin.
Third part of this research work focuses on the design and synthesis of 6-N-benzylated derivatives of 7-deazapurine nucleoside antibiotics, such as tubercidin, sangivamycin and toyocamycin. Target molecules were synthesized by two methods. First method involves treatment of 7-deazapurine substrates with benzylbromide followed by dimethylamine-promoted Dimroth rearrangement. The second method employs fluoro-diazotization followed by SNAr displacement of the 6-fluoro group by a benzylamine. The 6-N-benzylated 7-deazapurine nucleosides showed type-specific inhibition of cancer cell proliferation at micromolar concentrations and weak inhibition of human equilibrative nucleoside transport protein (hENT1).
In the fourth part of this dissertation, syntheses of C7 or C8 modified 7-deazapurine nucleosides, which might exhibit fluorescent properties, were undertaken. 8-Azidotoyocamycin was synthesized by treatment of 8-bromotoyocamycin with sodium azide. Strain promoted click chemistry of 8-azidotoyocamycin with cyclooctynes gave the corresponding 8-triazolyl derivatives. Alternatively, 7-benzotriazolyl tubercidin was synthesized by iodine catalyzed CH arylation of tubercidin with benzotriazole.
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Verespy, Stephen S. III. "Probing Allosteric, Partial Inhibition of Thrombin Using Novel Anticoagulants." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4431.
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Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an alternative mechanism called allosteric, partial inhibition, that has shown promise to truly regulate coagulation. Partial inhibition through allosteric mechanisms are well described for membrane-bound and oligomeric proteins. However proteases, specifically monomeric proteases (i.e., thrombin), have not shown this phenomenon until now. A small library of coumarin-based sulfated allosteric modulators (CSAMs) was synthesized to target a surface region called exosite 2; mainly composed of highly positively charged residues surrounded by hydrophobic patches. Studies revealed a non-competitive mechanism of binding with a range of IC50s between 0.2-58 µM combined with inhibitory efficacies (ΔY) between 22-73%; indicative of allosteric, partial inhibition. The KD was determined for the most potent compound (3g; IC50 = 0.2 µM, ΔY = 47%) at 0.15 µM. 3g was observed to bind at exosite 2 through unfractionated heparin competition and thrombin mutant studies. Additional computational studies were in agreement with the mutant and competition studies, showing the sulfate of 3g binding within a pocket containing R126 and R233. Fluorescence quenching and antithrombin inactivation rate studies described a conformational change to thrombin’s active site in the presence of 3g, supporting reduction of thrombin’s catalytic efficiency, without complete inhibition of thrombin’s proteolytic activities. Coupled enzyme assays and gel electrophoresis showed that in the presence of 3g, hydrolysis of fibrinogen (IC50 = 0.51 µM, ΔY = 94%) and protein C activation (IC50 = 1.7 µM, ΔY = 91%) is fully inhibited. Alternatively, FXIII activation was shown to be only partially inhibited by the presence of 3g, and FXI activation did not show any significant activation or inhibition. 3g was also shown to be active in human plasma and whole blood, but requiring much higher concentrations to induce an anticoagulant effect. Mice studies looking at the effects of 3g in vivo showed that even at high concentrations, showed no abnormal bleeding or any other irregularities. This work highlights a novel occurrence regarding thrombin’s allosteric functionality against multiple endogenous substrates. This library of compounds may be useful in the future development of allosteric inhibitors and probes that pose little to no risk of bleeding events by inducing partial inhibition.
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Waterfield, P. C. "Novel C-organostannyl heterocycles." Thesis, University of Bath, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384138.
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Badyal, Karanbir. "The use of organotellurium heterocycles as precursors for novel organometallic compounds." Thesis, Aston University, 1996. http://publications.aston.ac.uk/9690/.
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The reactions of group 16 heterocycles with organometallic reagents are described. Thiophenes have been used as models for organic sulfur in coal and their reactivity towards triiron dodecacarbonyl has been investigated. Reaction of unsubstituted thiophene with Fe3(CO)12 results in desulfurisation of the heterocycle, with the organic fragment being recovered in the form of the ferrole, C4H4.Fe2(CO)6. In addition a novel organometallic compound of iron is isolated, the formula of which is shown to be C4H4.Fe3(CO)8. Bezothiophene reacts with Fe3(CO)12 to yield benzothiaferrole, C8H6S.Fe2(CO)6, in which the sulfur is retained in the heterocycle. Dibenzothiophene, a more accurate model for organic sulfur in coal, displays no reactivity towards the iron carbonyl, suggesting that the more condensed systems will desulfurise less readily. Microwave methodology has been successful in accelerating the reactions of thiphenes with Fe3(CO)12. However, reaction of benzothiphene does not proceed to the desulfurisation stage while dibenzothiphene is unreactive even under microwave conditions. Tellurophenes (Te analogues of thiophenes) are shown to mimic the behaviour of thiophenes towards certain organometallic reagents with the advantage that their greater reactivity enables recovery of products in higher yields. Hence, reaction of tellurophene with Fe3(CO)12 again affords the ferrole but with an almost ten-fold increase in yield over thiophene. More significantly, dibenzotellurophene is also detellurated by the iron carbonyl affording the previously inaccessible dibenzoferrole, C12H8.Fe2(CO)6, thereby demonstrating the mechanistic feasibility of dechalcogenation of the more condensed aromatic molecules. The potential of tellurium heterocycles to act as precursors for novel organometallics is also recognised owing to the relatively facile elimination of the heteroatom from these systems. Thus, 2-telluraindane reacts with Fe3(CO)12 to yield a novel organometallic compound of formula C16H16.Fe(CO)3, arising from the unsymmetric dimerisation of two organic fragments.
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Kilburn, John Paul. "Novel solid-phase synthesis strategies for the preparation of heterocycles and guanidines." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247056.
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Cabarrocas, Duran Gemma. "Aproximacions sintètiques per a la preparació estereoselectiva de noves quinolil i pirazolilglicines i per a la preparació en fase sòlida de llibreries de benzotiazoles, 1,2,4-triazines i benzimidazoles." Doctoral thesis, Universitat de Girona, 1999. http://hdl.handle.net/10803/8057.
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El treball experimental que ha permès redactar la present Tesi Doctoral ha estat dividit en dues parts. A la primera part es presenten els resultats referents a la síntesi estereocontrolada de noves heteroarilglicines (quinolil i pirazolilglicines) a partir de cetones acetilèniques, substrats quirals que permeten accedir a l'esquelet de diferents heterocicles (quinolines i pirazoles), la posterior obtenció dels corresponents quinolil i pirazolil--aminoalcohols i les diferents metodologies d'oxidació per tal d'accedir a les corresponents quinolil i priazolilglicines objectiu. A la segona part d'aquesta memòria s'ha estudiat, en dissolució, l'habilitat del grup alquilsulfona com a grup sortint eficaç en reaccions d'ipso-substitució nucleofilica. El desenvolupament d'aquesta reacció ha servit de punt de partida per a la creació de llibreries d'heterocicles amb alta diversitat molecular i potencial interès biològic sobre fase sòlida.These work have been divided in two sections. In the first section, a new and efficient methodology towards the stereocontrolled synthesis of novel -acetylenic ketones containing a masked -amino acid functionality in enantiomerically pure form has been developed. This new chiral building block is the starting material for the synthesis of enantiomerically pure quinolyl and pyrazolylglycines, important structures with potential biological activity and very useful for the synthesis of peptidomimetics. The methods begins from the Garner's aldehyde and takes place through an alkyne derivative via a carbonyl-alkyne homologation reaction. Condensation of the lithium acetylide at low temperatures with different aldehydes yielded the corresponding propargyllic alcohol derivatives in good yields, which under mild oxidative conditions gave the corresponding acetylenic ketones algmost quantitatively.In the second part of this work, the ability of alkylsulfonyl groups as efficient leaving groups in heteroaromatic mucleophilic ipso-substitution reactions has been studied. The rational behind this study has been the possibility of transferring the developed methodology to the solid support and thus to synthesize in a parallel fashion a small library of molecularly diverse heterocycles with potential biological interest. An in solution optimised methodology has been successfully transferred to the solid support and a small library of molecularly diverse benzothiazoles (-excedent heterocylces) was prepared in a parallel fashion in good overall yields and purities of the final products.
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Ros, Blanco Laia. "Disseny i síntesi de noves quimioteques de potencials inhibidors d’entrada del VIH." Doctoral thesis, Universitat Ramon Llull, 2011. http://hdl.handle.net/10803/31981.
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El programa de la síndrome de la immunodeficiència adquirida (SIDA o sida) de les Nacions Unides va estimar a finals de 2008 que més de 33 milions de persones arreu del món vivien amb el virus de la immunodeficiència humana (VIH). En l’estudi de les dianes terapèutiques contra l’agent etiològic de la sida s’han validat com a tals els coreceptors CXCR4 i CCR5 d’unió i fusió del virus a la cèl•lula hoste. Actualment hi ha un inhibidor d’entrada i un de fusió per al tractament de la infecció per aquest retrovirus, tot i que cap d’ells inhibeix el coreceptor CXCR4. Això, unit a la capacitat del virus de desenvolupar resistència als fàrmacs actuals, fa necessària la cerca de noves famílies de compostos que hi facin front.
El Grup d’Enginyeria Molecular (GEM) de l’IQS ha descrit prèviament una quimioteca combinatòria d’anàlegs de l’AMD3100, el cap de sèrie més actiu, formats per unitats estructurals polinitrogenades (que consisteixen en un heterocicle nitrogenat, un seguit de baules metilèniques i un grup amina primària terminal) unides a un espaiador p xililènic. La selecció d’aquesta quimioteca va dur a la identificació d’un nou candidat amb dos centres quirals amb activitat submicromolar contra el VIH. Aquest treball presenta diverses modificacions estructurals sobre ambdós caps de sèrie, en la cerca de nous inhibidors potencials del coreceptor d’entrada CXCR4.
En primer lloc, per tal de rebaixar la basicitat de l’AMD3100, s’han substituït els seus anells ciclàmics per sistemes pirido[2,3 d]pirimidínics, en la síntesi dels quals es té molta experiència en el GEM. La baixa solubilitat en dissolvents comuns d’alguns dels compostos obtinguts es presenta com un greu inconvenient per al seu desenvolupament com a fàrmac.
D’altra banda, tenint en compte el disseny racional descrit anteriorment al grup de recerca, s’amplia la quimioteca amb l’objectiu d’avaluar l’efecte de la distància entre àtoms de nitrogen i la presència de major impediment estèric entre l’espaiador aromàtic i el nitrogen que hi està directament unit. Tot i que no s’ha aconseguit millorar l’activitat del cap de sèrie, els compostos obtinguts presenten activitats prou satisfactòries. Igualment, s’obtenen els tres estereoisòmers del cap de sèrie amb activitat submicromolar i se n’avalua l’activitat antiviral per separat.
Finalment, es duu a terme un disseny de novo de fàrmacs basat en l’estructura per buscar nous candidats que permetin obrir la porta a altres famílies de compostos amb activitat anti-VIH, a través de l’enumeració de la quimioteca virtual, la selecció i la posterior síntesi.El programa del síndrome de la inmunodeficiencia adquirida (SIDA o sida) de las Naciones Unidas estimó a finales de 2008 que más de 33 millones de personas en todo el mundo vivían con el virus de la inmunodeficiencia humana (VIH). En el estudio de las dianas terapéuticas contra el agente etiológico del sida se han validado como tales los correceptores CXCR4 y CCR5 de unión y fusión del virus a la célula huésped. Actualmente existe un inhibidor de entrada y uno de fusión para el tratamiento de la infección por este retrovirus, aunque ninguno de ellos inhibe el correceptor CXCR4. Ello, unido a la capacidad del virus de desarrollar resistencia a los fármacos actuales, hace necesaria la búsqueda de nuevas familias de compuestos que le hagan frente. El Grup d’Enginyeria Molecular (GEM) del IQS ha descrito previamente una quimioteca combinatoria de análogos del AMD3100, el candidato más activo, formados por unidades estructurales polinitrogenadas (que consisten en un heterociclo nitrogenado, una serie de eslabones metilénicos y un grupo amina primaria terminal) unidas a un espaciador p xililénico. La selección de esta quimioteca llevó a la identificación de un nuevo candidato con dos centros quirales con actividad submicromolar contra el VIH. Este trabajo presenta diversas modificaciones estructurales sobre ambos candidatos, en la búsqueda de nuevos inhibidores potenciales del correceptor de entrada CXCR4. En primer lugar, para rebajar la basicidad del AMD3100, se han substituido sus anillos ciclámicos por sistemas pirido[2,3 d]pirimidínicos, en la síntesis de los cuales se tiene mucha experiencia en el GEM. La baja solubilidad en disolventes comunes de algunos de los compuestos obtenidos se presenta como un grave inconveniente para su desarrollo como fármaco. Por otra parte, teniendo en cuenta el diseño racional descrito anteriormente en el grupo de investigación, se amplía la quimioteca con el objetivo de evaluar el efecto de la distancia entre átomos de nitrógeno y la presencia de mayor impedimento estérico entre el espaciador aromático y el nitrógeno que está directamente unido a él. Aunque no se ha conseguido mejorar la actividad de la estructura de referencia, los compuestos obtenidos presentan actividades satisfactorias. Asimismo, se obtienen los tres estereoisómeros del candidato con actividad submicromolar y se evalúa la actividad antiviral por separado. Finalmente, se lleva a cabo un diseño de novo de fármacos basado en la estructura para buscar nuevos candidatos que permitan abrir la puerta a otras familias de compuestos con actividad anti-VIH, a través de la enumeración de la quimioteca virtual, la selección y la posterior síntesis.
The Joint United Nations Programme on Acquired Immunodeficiency Syndrome (AIDS) estimated in 2008 that more than 33 million people around the world lived with the human immunodeficiency virus (HIV). HIV cell fusion and entry coreceptors CXCR4 and CCR5 have been validated as targets for therapeutic intervention. Nowadays, there is one entry and one fusion inhibitor available for the treatment of this retrovirus infection, although none of them inhibits CXCR4 coreceptor. Due to this fact, added to the virus’ capacity of developing resistance to actual drugs, the search of new families of compounds facing up to these situations becomes necessary. The Grup d’Enginyeria Molecular (GEM) at IQS previously described a combinatorial library of analogues of the currently most active lead AMD3100, whose polinitrogenated building block consisted of a nitrogen-containing heterocycle, a saturated chain spacer and a terminal primary amine group, bonded to a p xylylene spacer. Library selection led to the identification of a new lead with two chiral centres and submicromolar activity against HIV. This work presents various structural modifications on both leads, looking for new potential CXCR4 inhibitors. First of all, in order to reduce basicity of AMD3100, cyclam rings were substituted by pyrido[2,3 d]pyrimidinic systems, whose synthesis has been widely studied at GEM. Low solubility in common solvents of some of the obtained compounds remains as a great inconvenience for their development as a drug. Furthermore, regarding the rational design previously described by the research group, the library has been expanded with the aim of evaluating the effect of the distance between nitrogen atoms and the steric effects between the linker and the nitrogen atom directly connected to it. Although biological activities do not improve the lead’s one, the obtained compounds present interesting activities. Moreover, the three stereoisomers of the lead compound with submicromolar activity have been synthesised and their activity has been evaluated separately. Finally, a de novo structure based drug design has been carried out looking for new hits allowing to identify new families of compounds with anti-HIV activity, by enumeration of the virtual library, selection of candidates and their synthesis.
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Khramov, Dimitri Mikhailovich 1981. "Novel N-heterocyclic carbenes: applications in materials chemistry and catalysis." Thesis, 2008. http://hdl.handle.net/2152/4006.
Full textAbstract:
A unifying theme of the chemistry presented is the synthesis, study, and application of a novel N-heterocyclic carbenes. Pursuit of these materials has resulted in new advances in carbene structure and bonding, the discovery of highly-efficient reactions, and the development of new polymers with unusual properties.text
35
An, Deqiang. "Novel calixpyrrole-like anion receptors." Thesis, 2004. http://hdl.handle.net/2152/1183.
Full text
36
An, Deqiang Sessler Jonathan L. "Novel calixpyrrole-like anion receptors." 2004. http://wwwlib.umi.com/cr/utexas/fullcit?p3139181.
Full text
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Hlungwani, Isaac. "Design, synthesis and biological evaluation of novel tetrasubstituted quinoline-3-carboxamides derivatives." Diss., 2020. http://hdl.handle.net/11602/1558.
Full textAbstract:
MSc (Chemistry)Department of Chemistry
Quinolines are well known naturally occurring heterocyclic compounds with nitrogen as a heteroatom. Quinolines are also one of the major classes of naturally occurring compounds and the interest in their chemistry is due to the wide range of their biological activities. The objective of the project was the synthesis of novel tetra-substituted quinoline-3carboxamides and subsequent transformation to other novel derivatives and evaluation of their biological activities against malaria and cytotoxicity. In achieving the objective, 2-chloroquinoline-3-carbaldehyde analogues 54A-G were synthesised from the reaction of acetanilides 53A-G and acetic acid. Knoevenagal reaction of 2chloroquinoline-3-carbaldehydes 54A-G with thiazolidinedi-2,4-one 62 provided 2chloroquinoline-3-methylene thiazolidinedi-2,4-one 55A-G which then underwent nucleophilic substitution reaction with sodium azide and afforded (Z)-5-((tetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56A-F. (Z)-ethyl-2-(2-5-((7bromotetrazolo [1,5a] quinolin-4-yl) methylene-2,4-dioxothiazolidin-3-yl) acetamido) acetate 57 was synthesised from the reaction of (Z)-5-((7-bromotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56D and ethyl-2-(2-chloroacetamido) acetate 65. The structures of the compounds were characterised by 1D NMR (1H, 13C, and DEPT 135), IR spectroscopy, elemental analysis and high-resolution mass spectroscopy. Novel selected synthesised quinoline compounds were evaluated of in vitro for two biological assays; namely anti-malarial activity and cytotoxicity. The anti-malaria activities of the novel quinoline compounds against 3D7 strain of the malaria parasite Plasmodium falciparum displayed that 2,6-dichloroquinoline-3-methylene thiazolidinedi-2,4-one 55C, (Z)-5-((7-fluorotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56B and (Z)-5((7-ethoxytetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56F are potential malaria drugs since they reduced the percentage parasite viability to 25.80, 12.40 and 20.40 respectively. These results were further substantiated by their IC50 values 0.40, 0.04 and 0.50 µg/mL. Compound 56B displayed the highest cytotoxicity activity against human cervix adenocarcinoma cells displaying percentage viability of 14.22 %. Compounds 56F and 56C displayed moderate cytotoxicity activity at 56.60 and 59.81 % viability.
NRF
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Johnson, Myron Mario. "The development of novel synthetic methodology for the synthesis of oxygenated heterocycles." Thesis, 2014. http://hdl.handle.net/10539/14963.
Full textAbstract:
A number of oxygenated heterocycles have been described in nature as having a myriad of biological activities. Owing to these biological activities and their complex structure, these compounds are of interest to us and the preparation of selected oxygenated heterocycles is described in this thesis. Three main sections form this thesis, with each representing a class of oxygenated heterocycle.
The first part of the thesis deals with pyranonaphthoquinone analogues where a model study was performed to construct the skeleton of the isochromane kalafungin. The synthesis of isochromane 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one was successfully achieved from commercially available 2,5-dihydroxybenzoic acid in an overall yield of 9.5%. The key steps employed in the synthesis of the isochromane were a cross metathesis reaction between (2-allyl-3,6-dimethoxyphenyl)methanol and ethyl acrylate to afford the α,β-unsaturated ester (E)-ethyl-4-(2-(hydroxymethyl)-3,6-dimethoxyphenyl)but-2-enoate which, after several synthetic steps, was converted to the isochromane via a radical induced lactonization using a hypervalent iodine reagent. The success of this route led us to the preparation of iscochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9b-tetrahydro-2Hfuro[ 3,2-c]isochromen-2-one. Our initial aim was to enzymatically resolve intermediate racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol, however, the use of Candida antarctica lipase B (CALB) to facilitate the kinetic resolution was not as successful as we hoped. Therefore, using racemic alcohol 1-(2-allyl-3,6-dimethoxyphenyl)ethanol and the key reaction conditions developed in the model study of 6,9-dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-c]isochromen-2-one, we successfully prepared isochromane (3aR, 5R, 9bR)-6,9-dimethoxy-5-methyl-3,3a,5,9btetrahydro 2H-furo[3,2-c]isochromen-2-one in an overall yield of 0.4%, albeit racemically. The second part of this thesis involved the use of nitroalkanes as precursors to spiroketals. In this section, we managed to successfully elucidate the mechanism of a novel Nef reaction previously described in our laboratories using three different substrates. The key steps involved during the elucidation of the mechanism were a Henry condensation reaction and a key modified Nef reaction. The preparation of the spiroketal skeleton of the griseusins was also attempted.
The last part of this PhD thesis focused on the formation of angucycline analogues, specifically analogues related to the landomycins. We have successfully managed to prepare landomycin analogues tetraphene-7,12-dione, 3-methoxytetraphene-7,12-dione and 3,8-dimethoxytetraphene-7,12-dione. A Suzuki reaction followed by a Wittig reaction, isomerisation and final ring closing metathesis allowed for the smooth preparation of these analogues. The preparation of related analogues bearing seven-membered rings has also been achieved and is described.
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Kamplain, Justin Wade 1980. "Novel N-heterocyclic carbene architectures for use in carbene based polymers and redox swithcable : catalysis." 2008. http://hdl.handle.net/2152/17900.
Full textAbstract:
The central focus of this dissertation pertains to the synthesis and study of novel N-Heterocyclic carbene architectures. This pursuit has led to advances in carbine structure and bonding, and application of NHCs in materials chemistry in the role of monomer and catalysttext
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Ferreira, João Paulo de Sousa. "Novel heterocyclic quinoline/quinolone-based compounds as acetylcholinesterase inhibitors and antioxidant agents." Master's thesis, 2019. http://hdl.handle.net/10773/30140.
Full textAbstract:
Alzheimer’s disease represents about 60-80% of all cases of dementia, mainly
affecting people over 65 years. This pathology is caracterizated at the molecular
level by the presence of senile plaques (Aβ amyloid peptides aggregates) and
neurofibrillary tangles (NFTs). In addition, several experimental studies have
revealed that acetylcholinesterase (AChE) enzyme plays a crucial role in the
development of Alzheimer’s disease, leading to the formation of NFTs and senile
plaques. Oxidative stress is a cause and consequence of this pathology,
activating signalling pathways that promote Aβ peptides aggregation, which in
turn are detected by microglia cells, leading to the formation of free radicals,
including NO•
, which, in turn, contributes to the marked neuroinflammation in this
pathology. In this context, the development of AChE inhibitors and antioxidants,
namely as radical scavengers, continue to deserve attention from researchers.
The aim of the present work was the synthesis, structural characterization
(mono-(
1H and 13C) and two-dimensional (HMBC and HSQC) nuclear magnetic
resonance (NMR) spectroscopy, mass spectrometry, high resolution mass
spectrometry and x-ray) of (aryl)(furo [3,2-c] quinolin-2-yl)methanones, 3-(3-aryl4,5-dihydro-1H-pyrazol-5-yl)-4-chloroquinolines and, as exploratory approach,
(E)-3-(2-hydroxyphenyl)-5-(4-methoxystyryl)isoxazole for the evaluation of AChE
inhibitory activity and antiradical activity.
The anticholinergic and antiradical activities of the synthesized compounds were
evaluated using Ellman's method and radical scavenging assays for (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+•
) and NO•
, respectively.
Whenever possible, the obtained values were expressed as a function of the
concentration of compound which promoted 50% of inhibition of enzymatic
activity or promoted 50% of radicals scavenging (IC50), respectively, to establish
some biological structural-activity relationships.
(Aryl)(furo[3,2-c]quinolin-2-yl)methanones were not effective as antiradical
agents, however two derivatives exhibited AChE inhibitory activities (IC50 < 100
µM). 3-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-4-chloroquinolines and (E)-3-(2-
hydroxyphenyl)-5-(4-methoxystyryl)isoxazole were good ABTS+• scavenger
agents but were not very effective in NO• scavenging, presenting for most
derivatives IC50 > 700 µM. 3-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-4-
chloroquinolines showed promising AChE inhibitory activities with most
derivatives having IC50 < 100 µM, while (E)-3-(2-hydroxyphenyl)-5-(4-
methoxystyryl)isoxazole was not very effective against this enzyme.
These results showed that some of the synthesized compounds have potential
as AChE inhibitors and antioxidant agents.A doença de Alzheimer representa cerca de 60 a 80% dos casos de demência afetando principalmente indivíduos com idades superiores a 65 anos. Esta patologia é caracterizada, a nível molecular, pela presença de placas senis (agregados de péptidos de Aβ amilóide) e agregados neurofibrilares (NFTs). Além disso, diversos estudos experimentais têm revelado que a enzima acetilcolinesterase (AChE) participa no desenvolvimento desta patologia, culminando na formação de NFTs e placas senis. O stress oxidativo é uma causa e consequência desta patologia, ativando vias de sinalização que promovem a agregação dos péptidos Aβ, que por sua vez, são detetados pelas células da microglia, levando à produção de radicais livres incluindo óxido nítrico (NO• ) que, por sua vez, contribuem para a neuroinflamação marcada nesta patologia. Neste contexto, o desenvolvimento de inibidores da AChE e de antioxidantes, nomeadamente como agentes captadores desses radicais, continuam a merecer atenção por parte dos investigadores. O presente trabalho teve por objetivo a síntese, caracterização estrutural (espectroscopia de ressonância magnética nuclear (RMN) mono- ( 1H e 13C) e bidimensionais (HMBC e HSQC), espetrometria de massa, espetrometria de massa de alta resolução e raio-x) de (aril)(furo[3,2-c]quinolin-2-il)metanonas, 3- (3-aril-4,5-di-hidro-1H-pirazol-5-il)-4-cloroquinolinas e ,a título exploratório, de (E)-3-(2-hidroxifenil)-5-(4-metoxiestiril)isoxazol para avaliação da atividade inibitória da AChE e antiradicalar. As atividades anticolinérgicas e antiradicalar dos compostos sintetizados foram avaliadas recorrendo aos métodos de Ellman e de avaliação da capacidade de captação dos radicais (ácido 2,2'-azino-bis(3-etilbenzotiazolina-6-sulfónico) (ABTS+•) e NO• , respetivamente. Sempre que possível, os valores obtidos foram expressos em função da concentração de composto que promoveu a inibição de 50% da atividade enzimática ou que promoveu 50% de captação dos radicais (IC50), respetivamente, para serem estabelecidas algumas relações estruturaatividade biológica. As (aril)(furo[3,2-c]quinolin-2-il)metanonas não se mostraram efectivas como agentes antiradicalares, no entanto dois derivados exibiram atividades inbitórias da AChE (IC50 < 100 µM). As 3-(3-aril-4,5-di-hidro-1H-pirazol-5-il)-4- cloroquinolinas e o (E)-3-(2-hidroxifenil)-5-(4-metoxiestiril)isoxazol foram bons agentes captadores do ABTS+• no entanto não foram muito efetivos na captação do NO• , apresentando para a maior parte dos derivados IC50 > 700 µM. As 3-(3- aril-4,5-di-hidro-1H-pirazol-5-il)-4-cloroquinolinas apresentaram atividades inibitórias de AChE promissoras com maior parte dos derivados apresentando IC50 < 100 µM, enquanto o (E)-3-(2-hidroxifenil)-5-(4-metóxiestiril)isoxazol não foi muito efetivo contra esta enzima. Os resultados evidenciaram que alguns compostos sintetizados apresentaram potencial como inibidores da AChE e como agentes antioxidantes.
Mestrado em Bioquímica
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Muñoz, Alberto. "The Development of Novel N-Heterocyclic Carbenes and Tools for Assessing Structural Variation Effects Upon Catalyst Reactivity." Thesis, 2018. https://doi.org/10.7916/D8N02QC9.
Full textAbstract:
N-Heterocyclic carbenes (NHCs) are an important class of compounds responsible for a wide variety of chemical transformations. NHCs may be used as organocatalysts that permit non-traditional carbon carbon bond formations due to their renowned ability to invert the electrophilic character of aldehyde carbonyl groups, a concept otherwise known as polarity reversal or umpolung reactivity. Despite their ubiquity with respect to accessing the umpolung of aldehydes, fundamental studies of these reactive species are still rather limited and narrow in scope. As a result, clarifying and solving problems relevant to umpolung-themed asymmetric catalysis becomes quite challenging. In this regard, our work has been focused on a three-pronged approach towards providing a more unified understanding of these complex catalytic systems. First, we describe the synthesis of unprecedented carboxylate-tethered triazolium NHCs and use them in the intramolecular Stetter reaction to understand their function. Second, we describe the acidities of a broad range of both chiral and achiral NHCs that have never had their acidities assessed before and use them to construct the first linear free-energy relationships of their kind. Finally, we develop a simple and noninvasive experimental protocol in which we can quickly benchmark the performance of a series of chiral catalysts by way of single competition experiments. We anticipate that these studies will have direct implications on the development of novel NHC-catalyzed reactions.
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Peters, Byron Kennedy. "Synthesis of novel tetrahydroisoquinoline chiral ligands for application in asymmetric transfer hydrogenation." Thesis, 2010. http://hdl.handle.net/10413/5428.
Full textAbstract:
Several tetrahydroisoquinoline (TIQ) diamine derivatives were prepared for use as ligands in asymmetric transfer hydrogenation (ATH) of acetophenone of which 17 intermediates and the eight target ligands were novel compounds. The initial design followed that of Noyori, who presented the efficiency of his monotosylated diamine in ATH. A series of eight novel secondary amine derivatives (78a-g and 88) were prepared with substituents that influenced the electronics and the sterics of and around the nitrogen donor. Ligand 71 was shown to have no activity for the ATH of acetophenone. It was apparent from experimental observations that a balance between the electronic and steric characteristics of the substituent was necessary to facilitate activity. It was found that ligand 78d possessing a benzyl group, had the greatest
activity (81 % conv.). The greatest selectivity was obtained with ligand 78f (77 % ee) having a chiral phenylmethyl substituent. It was discovered in the case of the active diamine ligands that an optimised 1500 equivalents of water was required in order to demonstrate any enantioselectivity. The exact role of the water has never been ascertained, although there are many publications in which the effect of water has been examined. The most active metal
precursor was also investigated and [RhCl2(Cp*)]2 was found to be the best for these TIQ diamine ligands in the specified model reactions. This work has recently been accepted for publication and has established criteria for further rational design on this system.Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.
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Moshapo, Paseka Thendo. "Synthesis of sulfoxide and sulfone mycothiol bioisosteres and novel carbohydrate-based thiochromans." Thesis, 2013. http://hdl.handle.net/10210/8754.
Full textAbstract:
M.Sc. (Chemistry)Inhibition of mycothiol biosynthesis pathway has attracted attention from chemists and biochemists who aim to develop novel anti-TB drugs. A possible route to inhibit the production of mycothiol in cells may be via the inhibition of enzymes involved in the biosynthetic pathways. Molecular analogues that mimic mycothiol and containing tetrahedral-forming functional groups have been reported to show activity against mycothiol biosynthesis by inhibiting the enzymes in the mycothiol biosynthetic pathway...
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"Synthesis of novel benzimidazole derivatives and their platinum (II) complexes." Thesis, 2010. http://hdl.handle.net/10413/2614.
Full textAbstract:
Benzimidazole and its derivatives have attracted many organic chemists due to their interesting biological activities. These include activities against viruses such as, HIV, RNA, herpes (HSV-1), influenza, and cytomegalovirus (HCMV); antimicrobial and antitumor activities. Even though a lot of research has been conducted on the synthesis of benzimidazoles, factors such as, drug resistance present a need for synthesis of more structural analogues of these compounds. In chapter three, the synthesis of 2-aryl-1Hbenzimidazoles (46a-c) and 2-aryl-1-arylmethyl-1H-benzimidazoles (49a-d) is described. The yields for these products ranged from 44-79 % and 62-72 %, respectively. The synthesis of novel bisbenzimidazole derivatives is described in chapter four. Direct condensation of 3,3'-diaminobenzidine (1 mmol) with 2-thiophenecarboxyaldehyde (2 mmol) afforded 2, 2’-di-2-thienyl-5,5-Bi-1H-benzimidazole (52) in 65 % yield. Except in the case of 2-furancarboxyaldehyde, the acid catalyzed condensation of 3,3'- diaminobenzidine (1 equivalent) and heteroaromatic aldehydes (4 equivalents) gave novel bisbenzimidazoles where the aldehyde added three times to 3,3'-diaminobenzidine. The four times addition product, 1,2-di-2-furanylmethyl-2,2-di-2-furanyl benzimidazole (53) was obtained in 53 % yield. On the other hand, the three times addition product, 1,2-di-2- pyrrolylmethyl-2,2-di-2-pyrrolyl (54); 1,2-di-2-thienylmethyl-2,2-di-2-thienyl (55); and 1,2-di-2-pyridylmethyl-2,2-di-2-pyridyl benzimidazoles (56) were obtained in 85, 12 and 10 %, respectively. Full characterization of bisbenzimidazoles (54-56) was achieved by 1H, 13C NMR and LCMS spectra. Although benzimidazoles have been proven to be active against various cancers, their use as ligands for platinum (II) has been reported to enhance this activity. Three new benzimidazole Pt (II) complexes were synthesized. N, N, N-bound Pt (II) complexes of 2- quinolyl-1-quinolylmethyl-1H-benzimidazole (60) and 2-pyridyl-1-pyridylmethyl-1Hbenzimidazole (63) were obtained in excellent yields of 82 and 72 %, respectively. S, Nbound Pt (II) complex of 2-thienyl-1-thienylmethyl-1H-benzimidazole (64) was isolated in 63 % yield. From 195Pt NMR spectra analysis, it was concluded that the method reported by Morgan and Burstall is more efficient for the synthesis of these complexes. In addition to 195Pt NMR, platination was also confirmed using 1H and 13C NMR spectra.Thesis (PhD.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.
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Nkosi, S'busiso Mfan'vele. "Synthesis of novel quinoline derivatives and their cytotoxicity in A549 lung cancer cells." Thesis, 2017. http://hdl.handle.net/10321/2675.
Full textAbstract:
Thesis submitted in fulfilment of the requirements for the Degree of Master's in Chemistry, Durban University of Technology, 2017.Quinoline and its derivatives represent an important class of nitrogen-containing heterocylces as they are useful intermediates in organic synthesis and possess a broad spectrum of biological activities, such as anti-asthmatic, anti-inflammatory and anti-malarial activity. Hence, synthesis of novel compounds with potent biological activities is important in medicine. Significant research is directed into the development of new quinoline based structures and new methods for their preparations. In the past, synthesis of complex molecules was accomplished by step-wise reaction. This was time consuming and yield was generally low. Nowadays, multi-component reactions (MCRs) are being used since three or more substrates can be reacted in a one-pot reaction. Therefore yields are higher and the reaction is more efficient. In this research investigation novel quinoline derivatives, using the multi-component reaction protocol, were synthesized. After characterization of the product by several spectroscopic techniques, the biological potential of these compounds were assessed using lung cancer cell lines, bacteria and molecular modeling in an enzymatic system. In the synthetic part of this study, the first step was the preparation of the starting compound 2- chloro-3-formyl quinoline for which the Vilsmeier-Haack cyclisation protocol was used. The cyclisation was carried out by combining DMF and POCl3 at 5°C to form an electrophile which then reacted in situ with N-phenylacetamide at 100ºC to afford 2-chloro-3-formyl quinoline in high yield (95%). This was followed by the synthesis of a series of novel quinoline derivatives in a MCR system comprising 2- chloro-3-formyl quinoline, malononitrile, aromatic amines and dimethyl acetylenedicarboxylate in the presence of a catalytic amount of triethylamine. Valuable features of this routine included high yields, extensive substrate range and straight forward procedures. Eight novel poly-functionalised dihydropyridine quinoline derivatives were synthesized, purified and characterized. The outline for the synthesis of poly-functionalised dihydropyridine quinoline derivatives is presented graphically in Scheme 1. Scheme 2 shows the eight compounds synthesized and used subsequently for further studies. . Step 1 CH3 a N O H CHO N Cl Step 2 CHO CN N Cl CN NH2 R O OCH3 b OCH3 O MeO2C MeO2C N Cl CN N NH2 R = m-CH3, o-OCH3, p-Cl, m,p-Cl, o-F, m-F, p-F R Reaction Conditions: a. DMF, POCl3 b. Et3N, EtOH Scheme 1: Graphical representation for the synthesis of poly-functionalised dihydropyridine quinoline derivatives The novel eight compounds were screened for their potential activity in lung cancer cell lines. A549 cells were incubated for 24 hours with a range of concentrations of each compound, in triplicate, in a micro-titre plate together with an untreated control. Each experiment was conducted twice on separate occasions; the results from the first set matched the repeated experiment. The cells were then incubated (37ºC, 5% CO2) with the MTT substrate for 4 hours. Thereafter all supernatants were aspirated and DMSO was added to the wells. Finally the optical density was measured at 570 nm at a reference wavelength of 690 nm with an ELISA plate reader. The net MTT dependant absorbance (optical density) of each sample was calculated by subtracting the average absorbance of the blank from the average absorbance of each sample. Data were represented as mean optical density plus or minus the standard deviation. Four of the synthesized compounds (A1-A8) were evaluated for their cytotoxicity activities. The anti-cancer assay indicated that poly-functionalised dihydropyridine quinoline compounds, A2, A3 and A4 have good potential as anti-cancer drugs. Among them, A2 and A4 proved to be dose dependent with A4 having the highest toxicity at 250 µM and A8 having the highest toxicity at 125, 250 and 500 µM, whereas A1, A5, A6 and A7 were not cytotoxic. O H3CO H3CO O N Cl CN NH2 O H3CO H3CO O N Cl CN N NH2 OCH3 O H3CO H3CO O N Cl CN N NH2 O H3CO H3CO O N Cl CN NH2 CH3 Cl A1 A2 A3 A4 O H3CO H3CO O N Cl CN N NH2 F O H3CO H3CO O N Cl CN N NH2 O H3CO H3CO O N Cl CN NH2 O H3CO H3CO O N Cl CN N NH2 F Cl F Cl A5 A6 A7 A8 Scheme 2: Structures of novel poly-functionalised dihydropyridine quinoline derivatives by MCRs Since molecular docking is a key tool in structural molecular biology and computer-assisted drug design, these compounds were subjected to molecular docking and the binding mode for the compounds, within the active site of the protein, was analyzed. Docking of A1 to Human mdm2 protein provided insights into the binding regions. Three hydrogen bonds were formed between GLU 25 (2.7 Å distance), LEU 27 (3.2 Å distance) and LEU 54 (3.2 Å distance) atoms with binding energy of -8.91 kcal/mol. Docking of A1 with Human mdm2 indicated the lowest binding energy thereby showing strong affinity of the ligand molecule with the receptor which has been stabilized by strong hydrogen bond interactions in the binding pocket. This confirms that A1 is a better inhibitor for E3 ubiquitin-protein ligase mdm2 than all the other compounds tested (A2-A8). Further, the eight novel poly-functionalised dihydropyridine quinoline derivatives were evaluated for their antibacterial activity. This was performed using the MABA method against three strains i.e. Gram negative; Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 25922) and Gram positive; Staphylococcus aureus (ATCC 29213) using the broth micro dilution method. Standard antibiotics (ciprofloxacin and nalidixic acid) were used as positive controls and DMSO was used as a negative control. The results obtained from the anti-bacterial assay showed that compounds A4, A7 and A8 have high activity, whereas A2 and A3 showed poor activity against all the tested bacterial strains. Compound A6 showed no activity against S. aureus and E. coli.
M
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Najir, Afraj Shakil, and Afraj Shakil Najir. "Development of A3 coupling and Strecker Reaction followed by 1,3 Dipolar Cycloaddition Reaction for Synthesis of Novel Fused Heterocyclic compounds." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/7czr68.
Full textAbstract:
博士國立東華大學
化學系
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The increasing environmental consciousness of the chemical community has led to the search for more efficient and environmentally friendly methods for chemical synthesis. This thesis describes the development of eco-friendly multicomponent coupling reactions and their utility in novel fused heterocyclic compounds synthesis. First chapter outlines a practical and efficient two-step protocol for the synthesis of several new fused triazoles. The first step involved AuBr3 catalyzed A3 coupling reaction at solvent-free condition to provide the requisite propargylamines with prominent features with high structural diversity, short reaction time, high diastereoselectivities and environmental benign. Further, propargylamines undergoes catalyst free intramolecular azide-alkyne cycloaddition reaction to give tricyclic fused triazoles with excellent yields and diastereoselectivity. Second chapter addresses a one-pot green and highly efficient method for the synthesis of propargylamines and diastereoselective synthesis of fused triazoles via A3 coupling reaction in the presence of Manganese(II) chloride as a catalyst and intramolecular [3+2] cycloaddition, respectively, without using a co-catalyst or activator is reported. This methodology is efficient, eco-friendly, operationally simple and effective for reactions involving aromatic, aliphatic, and heterocyclic aldehydes, and provides an easy access to propargylamines in excellent yields and fused triazoles in good yield and excellent diastereoselectivities. Third chapter highlights a method for the synthesis of propargylamines by a A3-coupling reaction followed by a [3+2] cycloaddition for the preparation of tricyclic fused triazoles. The A3 coupling uses Tin(II) chloride as the catalyst under solvent-free conditions to generate the desired products in good to excellent yields, this chapter also containes one more new method to synthesize series of novel isoxazoles through a Copper(II) acetylacetonate-catalyzed solvent-free A3 coupling reaction followed by intramolecular nitrile oxide-alkyne cycloaddition. This method demonstrates high structural diversity and generates desired products in satisfactory yields and diastereoselectivities. Fourth chapter describes efficient two-step method for synthesizing a series of new fused tetrazols by a catalyst-free three-component Strecker reaction followed by an intramolecular [3+2] cycloaddition. The first step involved three component coupling of aldehydes, (S)-2-(azidomethyl)pyrrolidine and potassium cyanide in presence of water to form aminonitriles. In the next step aminonitriles underwent intramolecular azide-nitrile cycloaddition to form fused tetrazoles. This methodology is cost-effective, operationally simple, and applicable for various aromatic, aliphatic and heterocyclic aldehydes, and gives desired products in satisfactory yields and diastereoselectivities.
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Vicente, V., A. Fruchier, M. Taillefer, C. Coombes-Chamelet, Ian J. Scowen, F. Plenat, and H.-J. Cristeau. "Synthesis and structural studies (H-1, C-13, P-31 NMR and X-ray) of new C-bonded cyclotriphosphazenes with heterocyclic substituents from novel phosphinic acid derivatives." 2004. http://hdl.handle.net/10454/3552.
Full textAbstract:
NoThree new C-bonded cyclotriphosphazenes, [N3P3(2-thienyl)6], 2, [N3P3(3-thienyl)6], 4, and [N3P3(3,3-bithienyl-2,2-ylene)3], 6, have been prepared by two new synthetic procedures and are the first examples of non-spiro and trispirocyclotriphosphazene derivatives composed of thiophene and 3,3-dithiophene substituents, respectively. Their 1H, 13C and 31P NMR parameters are given. The solid state structures of 2, 4 and 6 have been determined by X-ray crystallography.
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Machado, Vera Alexandra Pereira. "Synthesis of novel heterocyclic compounds based on rational design and evaluation of their antitumor and antiangiogenic potential in human endothelial and tumor cell lines with tyrosine kinase membrane receptors as targets." Doctoral thesis, 2016. http://hdl.handle.net/1822/44973.
Full textAbstract:
Tese de Doutoramento em Ciências - Especialidade em QuímicaThe synthesis of novel 1-aryl-3-[3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas was performed and they were first studied as potential antiangiogenics using Vascular Endothelium Growth Factor Receptor-2 (VEGFR-2) tyrosine kinase enzymatic assays. The most promising inhibitors, 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas, were also studied as antiangiogenics in endothelial cells (HUVECs) and as antitumorals against breast cancer cell lines. These compounds with the arylurea moiety in the metaposition relative to the thioether, showed the lowest IC50 values in enzymatic assays (10– 206 nM), the most potent compounds being those bearing hydrophobic groups (Me, F, CF3, CF3 and Cl) in the terminal phenyl ring (IC50 10–28 nM). A convincing rationalization as type II VEGFR-2 inhibitors was achieved by molecular docking, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta-position. For all the compounds prepared with this type of substitutions, significant inhibition of HUVECs proliferation, migration and tube formation were observed at low concentrations (1.0-2.5 µM). Total and phosphorylated (active) VEGFR- 2 were detected by Western blotting, being the receptor phosphorylation significantly inhibited by these compounds at the same concentrations. An increase of apoptosis was also observed using TUNEL assay. Altogether, these outcomes point to an important antiangiogenic effect of these compounds in HUVECs. The antiproliferative properties of the compounds bearing hydrophobic groups were evaluated against two human breast cancer cell lines: hormone-dependent MCF-7 (ER positive) and MDA-MB-231 (ER/PR/HER2 - triple negative), the latter resulting from one of the most aggressive breast carcinomas with poor prognosis. The tested compounds suppressed breast cancer cell viability, proliferation, migration and colony formation at low concentrations (0.5-2.5 µM), without showing cytotoxicity in non-neoplastic human breast epithelial cells (MCF-10A). At the same concentrations, they induced apoptosis in MDA-MB-231 but not in MCF-7, and inhibited PI3K/Akt and MAPK/Erk signaling pathways in both breast cancer cell lines as observed by Western blotting. The findings of this work reveal a dual antitumor and antiangiogenic activity that is of paramount importance to the development of novel therapeutic strategies against breast cancer, rendering these compounds a relevant breakthrough for cancer therapy.
Sintetizaram-se novas 1-aril-3-[3- ou 4- (tieno[3,2-b]piridin-7-iltio)fenil]ureias e foram inicialmente estudadas como potenciais antiangiogénicos, usando ensaios enzimáticos de tirosina quinase do "Vascular Endothelium Growth Factor Receptor-2" (VEGFR-2). Os inibidores mais promissores, 1-aril-3-[3-(tieno[3,2-b]piridin-7-iltio)fenil]ureias, foram também estudados como antiangiogénicos em células endoteliais (HUVECs) e como antitumorais em linhas celulares de cancro da mama. Estes compostos com o grupo arilureia em posição meta em relação ao tioéter, apresentaram os menores valores de IC50 nos ensaios enzimáticos (10-206 nM), sendo os compostos que possuem grupos hidrofóbicos (Me, F, CF3, CF3 e Cl) no anel fenilo terminal, os mais potentes (IC50 10-28 nM). A racionalização convincente como inibidores tipo II de VEGFR-2 foi obtida por “docking” molecular, com base na presença simultânea: (1) da ligação tioéter e (2) do grupo arilureia em posição meta. Para todos os compostos com este tipo de substituições, observou-se uma significativa inibição da proliferação, migração e formação de túbulos em HUVECs a baixas concentrações (1.0-2.5 µM). A forma total e fosforilada (ativa) do VEGFR-2 foram detetadas por Western blotting, sendo a fosforilação do recetor significativamente inibida por estes compostos nas mesmas concentrações. Um aumento da apoptose foi também observado, utilizando o ensaio de TUNEL. Em conjunto, estes resultados mostram que estes compostos têm um importante efeito antiangiogénico em HUVECs. As propriedades antiproliferativas dos compostos com grupos hidrofóbicos foram avaliadas em duas linhas celulares de cancro da mama: hormonodependente MCF-7 (ER positivo) e MDA-MB-231 (ER/PR/HER2 – triplo negativo), sendo a última resultante de um dos carcinomas da mama mais agressivo e de mau prognóstico. Os compostos testados suprimem a viabilidade celular, proliferação, migração e a formação de colónias a concentrações baixas (0.5-2.5 µM), sem citotoxicidade em células epiteliais humanas de mama (MCF-10A). Nas mesmas concentrações, estes compostos induziram apoptose em MDA-MB-231, mas não em MCF-7 e inibiram as vias de sinalização PI3K/Akt e MAPK/Erk em ambas as linhas celulares, conforme observado por Western blotting. Os resultados deste trabalho revelam uma dupla atividade antitumoral e antiangiogénica, que é de suma importância para o desenvolvimento de novas estratégias terapêuticas para o cancro da mama, tornando estes compostos um avanço relevante para a terapia do cancro.
Fundação para a Ciência e a Tecnologia (FCT) - Portugal for the financial support through the Portuguese NMR network (Bruker 400 Avance III - Univ. Minho), to FCT and FEDER (European Found for Regional Development)- COMPETE/QREN/EU for the financial support through the research project PTDC/QUIQUI/ 111060/2009, and also to FCT, my PhD grant (SFRH/BD/77373/2011) also supported by POPH-QREN and FSE.
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Sudhir, V. Sai. "Novel Strategies Towards Condenced Triazoles, Ferrocene Aminoacids, Conjugates And Selenosulfides." Thesis, 2009. http://hdl.handle.net/2005/1003.
Full textAbstract:
Chapter 1: Facile entry into triazole fused tetrahydropyrazinones from amines and amino acids.
In this chapter, A practical and high yielding regioselective synthesis of several new, enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones is described starting from primary amines in a three step reaction sequence (alkylation, acylation, one-pot displacement with azide followed by cycloaddition) employing constrained intramolecular ‘click’ reaction as the key step. The method obviates chromatographic purification of products.
This methodology was also extended to the synthesis of diverse triazole fused tetrahydropyrazinones derived from amino acids. The scope of this methodology was extended by varying the alkyl as well as acyl components which furnished other triazole fused novel heterocycles.
Chapter 2: Facile entry into triazole fused heterocycles via sulfamidate derived azido-alkynes.
Direct synthesis of condensed triazoles from diverse sulfamidates by ring opening of sulfamidates with sodium azide followed by one-pot propargylation and cycloaddtion furnished title compounds. The methodogy in general has been demonstrated on diverse sulfamidates derived from amino acids, amino acid derivatives to obtain a variety of triazole fused scaffolds.
In one example, a condensed triazole containing amino acid has been synthesized by ring opening of a sulfamidate derivative with propargyl amine. This methodology has also been extended to the synthesis of condensed triazoles derived from D-glucose.
Chapter 3: ‘Click Chemistry’ Inspired Synthesis of Novel Ferrocene-Amino acid, Peptide Conjugates.
In this chapter synthesis of a wide range of ferrocene-amino acid and peptide conjugates in excellent yield is presented. Conjugation is established via copper catalyzed Huisgen 1,3-dipolar cycloaddition. Two complementary strategies were employed for conjugation, one involving cycloaddition of amino acid derived azides with ethynyl ferrocene and the other involving cycloaddition between amino acid derived alkynes with ferrocene derived azides.
Labeling of amino acids at multiple sites with ferrocene is discussed. A new route to 1, 1’ unsymmetrically substituted ferrocene conjugates is reported. A novel ferrocenophane is accessed via bimolecular condensation of amino acid derived bis alkyne with azide.
The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry.
Chapter 4: Click Chemistry inspired Synthesis of Ferrocene Amino acids and other derivatives.
This work reports the synthesis of a wide range of ferrocenyl-amino acids and other derivatives in excellent yield.
Diverse amino acid containing azides were synthesized and ligated to ferrocene employing click reaction to access ferrocenyl amino acids. Chiral alcohols, esters, diols
amines containing azido group were tagged to ferrocene via click reaction to generateferrocene derived chiral derivatives. A novel strategy for direct incorporation of ferrocene
into a peptide and a new route to 1, 1’ disubstituted ferrocene amino acid derivative are reported. Synthesis of mono and disubstituted ferrocene derivatives employing ferrocene derived azides is also described.
Chapter 5: Convenient synthesis of Ferrocene Conjugates mediated by Benzyltriethylammonium Tetrathiomolybdate in a multi-step tandem process.
The synthesis of a wide range of ferrocene derived sulfur linked mono and disubstituted Michael adducts and conjugates mediated by benzyltriethylammonium tetrathiomolybdate in a tandem process is reported. New route to access acryloyl ferrocene and 1,1’-bis acryloyl ferrocene is discussed.
Conjugation of amino acids to ferrocene is established via their Nand Ctermini and also via side chain employing conjugate addition as key step to furnish monovalent and divalent conjugates. This methodology has also been extended to access several ferrocene carbohydrate conjugates.
The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry. Finally, 1,1’-bis acryloyl ruthenocene was synthesized and it was utilized for the preparation of ruthenocene-carbohydrate conjugate in good yield.
Chapter 6: Formation of Intramolecular S-Se bond mediated by tetrathiomolybdate.
In this chapter, we have disclosed our preliminary results on reactivity of tetrathiomolybdate towards compounds containing both thiocyanate and selenocyanate functionalities. Several such compounds have been synthesized from the corresponding dibromides in two steps.
We have observed selective reductive dimerization of selenocyanate over thiocyanate. In all the cases we also obtained seleno-sulfides via disulfide diselenide exchange reaction upon addition of excess tetrathiomolybdate.
In the case of substrates on benzene scaffold, disulfide and diselenide bridged macrocycles were obtained apart from seleno sulfides whereas in the case of ferrocene derived substrates, formation of macrocycles was not observed. A tentative mechanism for the formation of these novel seleno sulfides is also discussed.(For structural formula pl see the pdf file)