MSc (Chemistry) / Department of Chemistry / Chromones are well known naturally occurring heterocyclic compounds with oxygen as a heteroatom. Chromones are also one of the major classes of naturally occurring compounds, and the interest in their chemistry is due to their wide range of their biological activity. In this study, three classes of target compounds were synthesized through three different pathways. The first pathway, chromone-3-carbaldehyde analogues were afforded in good to excellent yield followed by the oxidation thereof to 4-oxo-4H-chromene-3-carboxylic acids. A series of chromone-3-carboxamides was obtained from corresponding 4-oxo-4H-chromene-3-carboxylic acid via the in situ generation of the corresponding acid chloride in good yield. The second class of compounds were achieved by reacting corresponding chromone-3-carbaldehyde analogues with thiazolidine-2,4-dione to afford 5-((4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues. The third class of compounds followed the same reaction pathway as the second class of compounds from corresponding 8-allyl-chromone-3-carbaldehyde analogues to afford 5-((8-allyl-4-oxo-4H-chromen-3-yl)methylene)thiazolidine-2,4-dione analogues in good yield. Compounds were characterized by 1D NMR (1H, 13C and DEPT), 2D NMR (COSY, HSQC and HMBC), IR and elemental analysis (CHN analysis). Selected synthesized chromone derivatives were evaluated in vitro for two biological assays; namely trypanocidal activity and cytotoxicity. Among all tested compounds, 41A, 55B and 63D displayed promising trypanocidal activity by reducing the percentage parasite viability to 0.61, 0.15 and 0.21 respectively. These results were further substantiated by their IC50 values 4.3, 1.3 and 1.9 μg/mL respectively. Compounds 41B and 59A also showed significant trypanocidal activity, however it was below the positive control. Compounds 41A and 55B displayed cytotoxicity against the HeLa cells whilst compound 63D displayed no toxicity against the HeLa cells. / NRF

L'un des défis actuels de la chimie alimentaire est de développer des produits avec une qualité sanitaire et sensorielle optimale. Ceci est particulièrement important dans les produits traités thermiquement, tels que les produits céréaliers. Lors de la cuisson et à partir des ingrédients, un nombre considérable de composés peuvent se former. Certains suscitent une préoccupation sanitaire émergente, lorsque d'autres jouent un rôle sensoriel indéniable. Comprendre la réactivité des constituants devient alors un levier puissant pour développer des voies d'amélioration des aliments. Ce travail porte sur les effets des ingrédients et conditions de cuisson dans la génération de furane, composé possiblement cancérigène, et furfural, composé odorant contribuant à l'arôme caractéristique de la génoise. Afin de maîtriser la réactivité et ainsi optimiser la qualité des produits, une approche globale a été adoptée, incluant l'étude des composés volatils, des propriétés physicochimiques et sensorielles et l'appréciation hédonique des consommateurs. Ce travail propose une méthodologie et ouvre des pistes intéressantes pour développer des stratégies efficaces de maîtrise de la qualité globale des produits transformés. / A current challenge for food chemists consists in developing safe yet appealing food. This is particularly difficult in thermally-treated foods, like baked products, since a great number of compounds may be produced during heating. While some of these are of health concern, others contribute to other key aspects of quality, such as aroma or color, revealing the need of considering reactivity into food quality design. This work deals with the effects of formulation and baking conditions on the generation of furan, a heatinduced contaminant, and furfural, contributing typical aroma to sponge cake. Moreover, a holistic approach was adopted, covering volatile generation, physical properties, sensory evaluation and consumer tests, both for further understanding reactivity and optimizing product quality. This work is certainly an important step towards the development of novel strategies for qualitydriven design of heat-treated food.

Text in English / Specially prepared 2-amino-5-bromo-3-iodoacetophenone and 5-bromo-2-hydroxy-3 iodoacetophenone were subjected to Claisen-Schmidt aldol condensation with benzaldehyde derivatives followed by sequential and/or one-pot palladium catalyzed Sonogashira cross coupling and heteroannulation of the 3-alkynylated intermediates to afford indole-chalcones and benzofuran-chalcones, respectively. The indole-chalcones derivatives were, in turn, subjected to trifluoroacetic anhydride in tetrahydrofuran under reflux to afford the corresponding 3-trifluoroacetyl substituted indole-chalcone derivatives. The coupling constant values (Jtrans) of about 16.0 Hz for the chalcone derivatives corresponding to the vinylic protons confirmed the trans geometry of the α,β-unsaturated carbonyl framework in all the cases. Their trans geometry of the chalcone derivatives was further confirmed by single crystal X-ray diffraction (XRD) analyses. Further structural elaboration of the ambident electrophilic α,β unsaturated carbonyl (chalcone) moiety of the indole-chalcones and the analogous benzofuran chalcones with 2-aminothiophenol afforded novel benzothiezapine-appended indole and benzofuran hybrids, respectively. Sonogashira cross-coupling of 5-bromo-2-hydroxy-3 iodoacetophenone with terminal acetylenes followed by heteroannulation of the intermediate 3-alkynylated 5-bromo-2-hydroxyacetophenones afforded the corresponding 7-acetyl-2-aryl-5-bromobenzofurans in a single-pot operation. The oximes derived from the 7-acetyl–substituted 2-aryl-5-bromobenzofurans were subjected to Beckmann rearrangement with triflic acid in acetonitrile under reflux. We isolated the corresponding 7-amino-2-aryl-5 bromobenzofuran derivatives formed from hydrolysis in situ of the intermediate 7-acetamide 2-aryl-5-bromobenzofurans. Amino-dechlorination of the 4-chloroquinazoline derivatives with the 7-aminobenzofurans afforded novel benzofuran 4-aminoquinazoline hybrids. The prepared compounds were characterized using a combination of nuclear magnetic resonance (1H-NMR & 13C-NMR including 19F-NMR), infrared (IR) and mass spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analyses and/or density functional (DFT) method. The benzofuran-chalcone 203a–y derivatives were evaluated for anti-growth effect against the breast cancer (MCF-7) cell line by the MTT cell viability assay. Their mode of cancer cell death (apoptosis versus necrosis) was detected by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The most cytotoxic compounds 203i and 203o were also evaluated for potential to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. The experimental results were complemented with theoretical data from molecular docking into ATP binding site of the EGFR and colchicine binding site of tubulin, respectively. The benzofuran–4-aminoquinazoline hybrids 215a–j, on the other hand, were evaluated for antiproliferative propeties in vitro against the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (C3A) cell lines. The benzofuran-aminoquinazoline hybrids were also evaluated for potential to induce apoptosis and for their capability to inhibit EGFR-TK phosphorylation complemented with molecular docking (in silico) into the ATP binding site of EGFR. Mechanistic studies demonstrated that the benzofuran-appended aminoquinazoline hybrids 215d and 215j induced apoptosis via activation of caspase-3 pathway. Moreover, compounds 215d and 215j exhibited significant and moderate inhibitory effects against EGFR (IC50 = 29.3 nM and 61.5 nM, respectively) when compared to Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 215 into EGFR-TK active site suggested that they bind to the region of EGFR like Gefitinib does. / Chemistry / D. Phil. (Chemistry)