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

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...

A number of biologically active chromones occur in plants (eg. Khellin) and research in this field has eventually led to the discovery of chromoglycic acid, which is widely used as a sodium salt in asthma therapy. Since biological activity may be related to acidity, a range of chromone-2-carboxylic acids have been prepared via Claisen acylation of substituted o- hydroxyacetophenones and their acid dissociation constants determined potentiometrically to explore substituent effects. From this study it has been found that introduction of certain groups does have a marked effect on acidity. A variety of acrylamide derivatives have been prepared via the dimethylamine-mediated ring opening of chromone-2-carboxamides which, in turn, were prepared from the chromone-2- carboxylic acids via the corresponding acid chlorides. Variable temperature NMR spectroscopy was employed to examine the effect of substituents on the rotational barriers and it has been found that for the acrylamides examined, ring substituents have little effect on the rotational barriers. A combination of low resolution, high resolution and meta-stable peak analysis has been used to study mass fragmentation patterns for a series of acrylamide derivatives. The proposed fragmentation pathways for selected peaks have been found to be common to all the spectra examined when differences in the atomic masses of substituents were taken into account.

This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

The chemistry of amino sugar compounds has been studied in the last years in connection with the study of natural products, and many of them have been isolated. 57,17,18 Amino sugars play an important role in biochemistry, forming blocks of homo- and heteropolymers and complex molecules such as microbial polysaccharides, enzymes, gangliosides, glycoproteins, and antibiotics. This research project had the purpose of preparing a derivative of 2-amino-2-deoxy-D-glucose, with a free hydroxyl group at the anomeric carbon, with the 4,6-positions blocked with the benzylidene cyclic acetal, and the 2,3-positions being blocked by a 3,3-diphenyl-2-morpholinone ring trans diequatorially fused to the amino sugar ring. The C-1 position was initially protected with a β-benzyl aglycon, which was expected to be removable selectively by catalytic hydrogenation. It was also hoped that we could optimize conditions for the synthesis of the morpholinone derivative. Selective cleavages of the blocking groups were to be investigated.

This dissertation summarizes my research in the Roy group on the development, synthesis, and study of new N-heterocyclic carbene (NHC) based ligands and nickel phsophinidene core compositions of molecular clusters, also known as superatoms. Chapter 1 introduces superatoms as atomically precise and discreet building blocks for use in the design and synthesis of novel materials. A brief history as well as selected synthetic strategies of superatoms will be introduced. The relevant materials properties of superatoms as well as their dependence on core composition and ligand structure will be discussed. Next, the use of superatoms with specialized or functionalizable ligands to synthesize new materials will be demonstrated. This chapter details the importance of the superatom ligands and core composition is the foundation that the subsequent chapters builds upon in developing these two areas. Chapter 2 introduces a functionalized NHC as a potential superatom ligand. While not necessary for all superatom ligands, ligands that enable electronic access to the superatom core are attractive. In this chapter, the conductance of potential NHC based ligands are probed through the scanning tunneling microscope-based break-junction (STM-BJ) method. A novel method of forming single molecule junctions in situ was used and these ligands are found to display a length dependent conductance with strong coupling to the Au electrode, confirming their potential use as ligands for superatoms. Chapter 3 describes the nature of the NHC–M bond in self-assembled monolayers (SAMs) on a Au(111) surface using high-resolution spectroscopy and theoretical calculations. This study was performed as a result of challenges and questions encountered during the work of Chapter 2. The results obtained from this study explore an important structure-function relationship of NHC ligands and have broader impact in materials chemistry beyond superatoms. Chapter 4 explores the synthesis of superatoms with NHC ligands beyond simple imidazolium-based NHCs. This chapter describes the two primary synthetic techniques used and the synthesis of NHC-ligated superatoms. This work is also ongoing and characterization is limited to crude single crystal X-ray diffraction structures and select NMRs. Finally, Chapter 5 details the use of uncommon organocyclophosphine reagents to synthesis novel nickel-phosphinidene molecular clusters, a potential new superatom. In this chapter the synthesis of a family of nickel-phosphinidene molecular clusters is described and studied. A potential application of these molecular clusters is explored through the thermolytic conversion to the industrially relevant Ni2P.

No description available.

Degradability of atrazine, cyanazine, and dicamba under methanogenic conditions was evaluated using serum bottle microcosms containing wetland soil inocula obtained from three different sites. Pesticides were monitored by high-performance liquid chromatography (HPLC) and the production of methane was measured with a gas chromatograph (GC). Dicamba was the most susceptible to degradation in the microcosms, followed by cyanazine. Atrazine was not degraded in the wetland soils. A dicamba-degrading methanogenic consortium was enriched from one of the initial wetland soil microcosms (Lawnes). Dicamba degradation was further examined using this consortium. Net methane production suggested that the aromatic ring was not degraded. Rates of dicamba degradation were enhanced with addition of 0.2 % yeast extract. Dicamba degradation was accomplished within 4 days compared to 22 days without yeast extract addition. The inability of the consortium to degrade the benzenoid ring was confirmed when no ¹⁴CO₂ was produced upon addition of [U-¹⁴C]dicamba to the cultures. Analysis of culture filtrate by HPLC revealed the presence of a possible metabolite that was aromatic in character. / Ph. D.

Activated dichloro- and difluoro- monomers are well known for the synthesis of high-performance polymeric materials through the use of aromatic nucleophilic displacement reactions. Here, novel activated difluoro monomers were synthesized using the well established chemistry of Reissert compounds. Difunctional bis(Reissert compound)s were synthesized by the reaction of 4-(pfluorobenzylisoquinoline) and trimethylsilyl cyanide with the following diacid chlorides: sulfonylbis(p-phenyleneoxy)dibenzoy chloride, oxybis (benzoyl chloride), and sulfonylbis(benzoyl chloride}. These aforementioned compounds were rearranged using NaH/THF to produce the desired diketones. Finally, difluorotetraketone monomers were produced by oxidation of the benzylic methylenes of the diketones. These reactions were evaluated by FTI R and 1 HNMR. These new activated heterocyclic difluorotetraketones are precursors to novel heterocyclic poly(ether ketones). / Master of Science

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