Submitted in fulfillment of the requirements of the Degree of Doctor of Technology: Chemistry,Durban University of Technology, 2014. / Aromatic heterocycles are highly important structural units found in a large number of biologically active natural compounds, pharmaceuticals and catalytic compounds. They have a crucial role in organic syntheses, which results in the generation of high value products. Among heterocycles, those containing nitrogen are the most indispensable structural motifs and are widely used against dreaded diseases such as Malaria, TB, HIV/AIDS and Cancer. The inclusion of highly electronegative atoms such as fluorine in these organic molecules render them very reactive towards proteins. Furthermore these molecules exhibit strong interactions with surfaces of quantum range particles of elemental gold. Various approaches for the synthesis of novel gold nanoparticles linked to potent bioactive molecules are documented and their application as drug delivery systems are of immense value to human health. Also many chemical and physical methods are available for the synthesis of gold, silver and palladium nanoparticles however these methods are usually laborious and produce toxic by-products. The green approach is to use plant extracts to synthesise various size and shape nanoparticles which could be used in biological and catalytic systems. A simple one-pot two component and three component reaction using formyl quinoline, 2-aminothiophenol, thiosemicarbazone and trifluoromethylbenzaldehyde as a reactant to synthesise quinoline, pyridine and pyran based bioactive small molecules; these products are a quinoline type bearing a benzothiazole moiety, quinoline thio semicarbazone ligand, fluorine substituted dihydro pyridine, fluorine substituted dihydropyran and fluorine substituted pyridine derivatives. In total, fifteen compounds were synthesized eleven of which were novel; all compounds were characterized by spectroscopic techniques. In vitro anti-bacterial activities of the synthesized compounds were investigated against a representative panel of pathogenic strains. Compounds 6, 7, 8, 11 and 13 exhibited excellent anti-bacterial activity compared with first line drugs. Potent p53–MDM2 interaction inhibitors 2-thio-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazone and fluorine substituted new pyridine scaffold were successfully identified by structure-based design. An efficient one-pot four component route to the synthesis of trifluorinated pyrrolophenanthroline and fluoroquinoline pyrrolophenanthrolines was designed. In this reaction 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ionic liquid (DMTIL) was used as a reaction medium; no catalyst was required. The structure of the pyrrolophenanthrolines was deduced by IR and NMR analysis. These compounds were studied with Bovine Serum Albumin (BSA) through molecular docking. Hydrophopic, electrostatic and hydrogen bonding interaction played a crucial role in the binding to sub domain of BSA. Interaction studies of DMTIL with BSA by emission, absorption, synchronous fluorescence, circular dichroism (CD) and three dimensional emission (3D) spectroscopic techniques were under taken. The results from emission titration experiments revealed the existence of a strong interaction between BSA and DMTIL ionic liquid. It showed that compounds with lesser number of hydrogen bonds are found to be more active which is attributed to hydrophobic interaction and electrostatic interaction which also played a vital role in DMTIL binding to sub domain IB of BSA. A novel copper-loaded boron nitride nanosheet (Cu/BN) catalyst was prepared and fully characterized. It was used as an efficient and chemoselective catalysts for the synthesis of α-aminophosphonates by the Kabachnik-Fields reaction; twenty one α-aminophosphonates were synthesised. The enhanced catalytic activity and product yield was attributed to the increase of surface acidity. Overall, this methodology offered competitive advantages such as recyclability of the catalyst without further purification or without using additives or cofactors, low catalyst loading, broad substrate applicability and high yields. The application of this new nanocatalyst in organic synthesis will provide a novel pathway for the synthesis of pharmaceutically important compounds. Gold nanoparticle surfaces were modified with self-assembled monolayers of important thiol and disulfide bioactive molecules since considerable interest is due to their potential application as anti-cancer agents. Herein, a carbazole was conjugated to lipoic acid by using an amide coupling catalyst HBTU and DIEA reaction. The structure of the carbazole thio octanic acid (CTN) was identified by IR and NMR. CTN was attached to the gold nanoparticles surface and the capping behaviour was characterized by UV-vis spectroscopy, TEM, DLS and FTIR. The cytotoxicity of CTNAuNPs on A549 cell lines was determined using the MTT assay. The results suggest CTN and CTNAuNPs possess anti-proliferative properties in the cancerous A549 cells. Furthermore a dual thiol ligand was synthesized by using equimolar 4-aminothiophenol (4-ATP) and amino oxadiazole thiol (AXT). This dual ligand was attached to the gold nanoparticles surface (DTAu) and the capping behaviour was characterized by UV-vis spectroscopy, TEM, DLS and FTIR. The cytotoxicity of DTAu on A549 cell lines was determined using the MTT assay. The results suggest dual ligands (4-ATP, AXT) and DTAu possess anti-proliferative properties in the cancerous A549 cells. South African indigenous plants and agroforestry waste were also used in the synthesis of silver, gold and palladium nanoparticles (NPs). Green protocols such as the use of environmentally benign solvents and non-hazardous reagents were an added advantage to physical and chemical means. Furthermore these reactions were rapid and the size and shape of the NPs could be manipulated by choosing the correct medium. The formulation of natural medicinal compounds capped onto NPs was assessed for their anti-cancer activity, in A549 lung cancer line, and catalytic reduction of dyes and nitrobenzene derivatives were studied. These NPs displayed: Significant cytotoxicity to lung cancer cells with minimal effect on normal healthy cells. Outstanding catalytic reduction of pharmaceutical and textile waste effluents such as dyes and nitro aromatic compounds. In addition, palladium nanoparticles containing capped Moringa olifera compounds were used effectively in the Suzuki coupling reaction of iodobenzene and phenylboronic acid. The reaction was rapid and was conducted in an aqueous medium.

Experimental mole fraction solubilities of benzil, thianthrene, trans-stilbene, thioxanthen-9-one, diphenyl sulfone and dibenzothiophene sulfone are determined in pure noncomplexing and complexing solvents. Predicted solubility values are calculated for benzil, thianthrene, trans-stilbene and thioxanthen-9-one using expressions derived from Mobile Order theory. Large deviations between experimental and predicted solubilities in alcohol solvents exist, therefore optimized solute - solvent association constants are determined. Previously measured thianthrene solubilities in five binary alkane + cyclohexane solvent mixtures are compared with values predicted from Mobile Order theory using the measured solubility in each of the pure solvents as input parameters. The experimental mole fraction solubility of benzil in eight binary alcohol + 1-octanol solvent mixtures are also measured and compared with predicted values.

Dans un contexte où il est préférable de limiter les quantités de principes actifs, aussi bien dans les médicaments que dans les produits phytosanitaires, il est important de développer des produits dont l’activité biologique est augmentée. Pour ce faire, il est possible d’utiliser des hétérocycles aromatiques contenant des groupements fluorés. Ainsi, nous nous sommes intéressés au développement de voies d’accès à des building blocks hétéroaromatiques portant divers groupements fluorés afin de fournir de nouvelles possibilités pour la préparation de composés d’intérêt thérapeutique et phytosanitaire. Trois projets ont été réalisés, et ont résulté en la préparation efficace de pyridines comportant des groupements trifluorométhoxy, chlorodifluorométhoxy et dichlorofluorométhoxy. Une voie de synthèse régiosélective de 3,5-bis(fluoroalkyl) pyrazoles a également été mise au point. Tous ces méthodes de synthèse ont été développées de manière à obtenir les produits en peu d’étapes à partir de produits commerciaux et sont transposables à grande échelle. / The current trend is to lower the amounts of active ingredients used, in pharmaceutical chemistry and in agrochemistry. Therefore, it is important to produce molecules which are more biologically active. It is known that heterocycles are bioactive, and that fluorine can enhance this activity. With this aim in mind, we have taken an interest in the development of heteroaromatic building blocks bearing diversely fluorinated substituents in order to provide new options for the preparation of bioactive compounds. Three projects have resulted in the opening of new synthetic routes towards pyridines bearing trifluoromethoxy, chlorodifluoromethoxy and dichlorofluoromethoxy substituents. A regioselective method for the preparation of 3,5-bis(fluoroalkyl) pyrazoles has also been developed. All these routes have been studied with the aim of obtaining the building blocks in a few steps from commercially available products and are transposable to an industrial scale.