A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Doctor of Philosophy Submitted June 2016. / The work detailed in this PhD involves two distinct, separate areas of research. The first project involved an investigation into the synthesis, characterisation and metal-chelation of pyrido-imidazo[1,2-a]pyridines in the search for new compounds for the treatment of cancer. Previously in our laboratories at the University of the Witwatersrand a small library of imidazo[1,2-a]pyridines were synthesized that showed significant activity (IC50 values between 6.57-21.98 μM) against Caco-2 and HT-29 colorectal cancer cell lines while showing little cytotoxicity towards white blood cells; significantly less than camptothecin the ‘golden standard’. In an attempt to improve the overall activity of the imidazo[1,2-a]pyridines methodology was developed to coordinate zinc, copper and platinum to the imidazo[1,2-a]pyridines to generate novel metal-imidazo[1,2-a]pyridine complexes. These novel compounds were characterised by NMR spectroscopy (where possible) and Single Crystal X-ray Diffraction (SCXRD) and tested against colorectal (Caco-2 and HT-29), leukemic (K562 and HL-60) and breast (MCF-7 and MDA-MB231) cancer cell lines, where the copper-containing compounds showed the most significant activity. A library of 11 copper complexes screened showed excellent activity in all the cell lines tested, some of which were more active than camptothecin. The second part of this PhD involved a detailed investigation into novel methodology to synthesize xanthones and related diones, for example such as 4a-methoxy-2H-xanthene-2,9(4aH)-dione, discovered in our laboratory. Initially this reaction was reported to be mediated by ceric ammonium nitrate (CAN), however it was determined during the course of this investigation that the novel reaction was actually mediated by ceric ammonium sulfate (CAS) and that different products were isolated depending on which reagent (CAN or CAS) was used. In this thesis, the mechanism of the reaction was probed and it was determined that the electronic nature of the starting benzophenone (e.g. (2-hydroxyphenyl)(2,4,6-trimethoxyphenyl)methanone) plays a crucial role in the outcome of the reaction. In addition to the furnishing of xanthones (e.g. 4-methoxy-9H-xanthen-9-one) and spirofurans (such as 2',6'-dimethoxy-3H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4'-dione) using this CAS-mediated reaction, novel biaryl-fused dimers (e.g. (4,4'-dihydroxy-[1,1'-biphenyl]-3,3'-diyl)bis((2,4-dimethoxyphenyl)methanone)) were also isolated and these results were explained by the mechanisms detailed in this work. Reliable methodology was developed using a sodium dithionite-mediated method for the conversion of dione products (such as 4a-methoxy-2H-xanthene-2,9(4aH)-dione) to hydroxy-containing xanthones (such as 7-hydroxy-9H-xanthen-9-one). iv Finally, as a proof of concept, this novel CAS-mediated methodology was extended to the synthesis of the nitrogen-containing derivatives, the acridones, and a single acridone, 10-benzyl-2-methoxyacridin-9(10H)-one, was successfully synthesized using CAS as the reagent, albeit in a low yield. / LG2017

Imidazo[1,5-a]pyridines are an important and versatile class of N-heterocyclic compounds due to their stability, unique biological, and photochemical properties. Due to the conjugation and charged structure, their properties are extended to conducting electricity and also have electronic properties. They can be used for chelating transition metals especially heavy metals that can be harmful to living things (including human). The aim of this research was to develop more useful imidazo[1,5-a]pyridines which are stable in both free and complexed state. A variety of imidazo[1,5-a]pyridyl compounds was synthesized following three useful methods namely (i) The first route includes the isolation of imine intermediates which were then treated with phosphorus oxychloride in one case and hydrochloric acid in another case as catalysts. Both cases resulted in the yield of the same imidazo[1,5-a]pyridyl compounds. (ii) The second route was the development on the first route for those imine intermediates that could not be isolated and only hydrochloric acid catalyst was used. In both the first and second routes, paraformaldehyde was used for the ringclosure step of the reaction. The last route for the formation of imidazo[1,5-a]pyridyl compounds did not involve the use of the paraformaldehyde reagent. The suitable routes were followed depending on the nature of the targeted products and the reaction yields were moderate to excellent. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg,2010.

Les produits appartenant à la famille des pyridopyrimidines sont caractérisés par leur intense utilisation dans le domaine pharmacologique, ce qui a poussé différentes équipes de recherche, de par le monde, à les étudier chimiquement et biologiquement. Dans ce travail, nous nous sommes intéressés au groupe des pyridopyrimidines et, plus particulièrement, à l’isomère le moins décrit dans la littérature, à savoir les pyrido[3,2-d]pyrimidines. Les composés ciblés sont synthétisés à partir de la 2,7-dichloropyrido[3,2-d]pyrimidine, via des substitutions nucléophiles aromatiques et des couplages pallado-catalysés et ce, dans le but d’obtenir de puissants inhibiteurs de kinases. Ce but a été atteint puisqu’en effet plusieurs des molécules élaborées inhibent les kinases testées avec des concentrations de l’ordre du nanomolaire. Des résultats pharmacologiques aussi concluants nous ont amenés à étendre nos études à d’autres pyridopyrimidines, à savoir les pyrido[2,3-d]pyrimidines ainsi qu’à d’autres types de bicycles polyazotés, en l’occurrence les imidazo[1,2-a]pyridines et les imidazo[1,2-b]pyridazines. / Products belonging to the pyridopyrimidine family are characterized by their intense use in pharmacology. The increase of interest for this heterocyclic scaffold prompted different research teams around the world to study their chemically and biologically properties. In this work, we are interested in the functionalization of pyridopyrimidines and, more specifically, of the less described regioisomer, namely pyrido[3,2-d]pyrimidines. The target compounds were synthesized from 2,7-dichloropyrido[3,2-d]pyrimidine via nucleophilic aromatic substitution and palladium-catalyzed couplings and, in order to obtain potent kinases inhibitors. Our goal has been achieved with several elaborate molecules. These bioactive compounds inhibit kinases such as Cyclin Dependant Kinases (CDK), Glycogen Synthase 3 (GSK3) or Dual specificity tYRosine-phosphorylation-regulated Kinase 1A (DYRK1A) in the nanomolar range. These biological targets are mainly involved in degenerative process or down syndrome. These pharmacological results led us to extend our studies to other pyridopyrimidines, namely pyrido[2,3-d]pyrimidines as well as other types of polynitrogenated bicycles, namely imidazo[1,2- a]pyridine and imidazo[1,2-b]pyridazine.