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Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first chapter of the thesis involves the design, synthesis, and anti-influenza activity of quercetin derivatives. Influenza viruses are important pathogens that cause respiratory infections in humans and animals. In addition to vaccination, antiviral drugs against influenza virus play a significant role in controlling viral infections by reducing disease progression and virus transmission. Plant derived polyphenols are associated with antioxidant activity, anti-carcinogenic, and cardio- and neuro-protective actions. Some polyphenols, such as resveratrol and epigallocatechin gallate (EGCG), showed significant anti-influenza activity in vitro. The antiviral effects of isoquercetin were greater than that of quercetin with lower IC[subscript]5[subscript]0 values and higher in vitro therapeutic index. Various phenolic esters, alkoxy and aminoalkoxy derivatives of quercetin were synthesized by functionalization of C3, C3’, and C5 hydroxyl groups. Antiviral activities of these synthesized compounds were tested against influenza virus (porcine H1N1 strain). Quercetin-3-gallate which is structurally similar to EGCG showed greater antiviral activity among the synthesized compounds. Its antiviral activity was comparable to that of EGCG with better in vitro therapeutic index. Second chapter in the thesis involves the progress towards the synthesis of mini graphenes like hexa-peri-benzocoronene cyclophane (HBCC). Bilayered graphenes are highly conducting materials with potential application in electronic devices and in lithium ion batteries. Despite great potential, bilayer graphenes with defined distance between the two layers have not been achieved through chemical synthesis. Chemical synthesis of hexa-peri-benzocorenene cyclophane (HBCC) from commercially available p-xylene was carried out. Final product, presumably compound 90 (the structure has not been completely characterized), is insoluble in all tested solvents including aqueous acids and organic solvents such as DMSO, DMF, benzene, 1,2-dichlorobenzene, dichloromethane, THF, hexanes and diethyl ether. The insoluble nature of the final product restricted the analysis to UV-visible spectroscopy. Synthesis of soluble analog incorporating the long chain ether groups is being investigated in Dr. Hua’s laboratory.

The cyto-protective compositions and effects of antiviral Maillard reaction products (MRPs) derived from roots of Isatis indigotica F. were examined using biochemical and biophysical methods. The Maillard reaction was identified as the main source of compounds with antiviral activity, an observation which has led to the proposal of a new class of active compounds that protect cells from influenza virus infection. In the roots, arginine and glucose were revealed to be the predominant reactants for the Maillard reaction. Significant anti-influenza virus effects were demonstrated in the RIE MRPs derived from the roots (RIE refers to the ‘radix Isatidis extracts’), and in Arg-Glc MRPs which are synthesised with arginine and glucose. Arg-Glc MRPs were confirmed as suitable models for the study of the antiviral effects of the root extracts. Furthermore, RIE MRPs and Arg-Glc MRPs were found to bind to the plasma membranes of erythrocytes and MDCK cells, and altered their properties. A novel antiviral mechanism was proposed: that MRPs achieve their cyto-protective effects by binding to the cell membrane rather than by direct action on viral particles. To validate the proposed mechanism, the interaction between MRPs and membrane lipids was investigated by biophysical experiments with phospholipids bilayers. Arg-Glc MRPs affected the rigidity of lipid packing in monolayers and bilayers, while RIE MRPs enhanced the fluidity. Both types of MRPs inserted into the hydrophobic core of bilayers, to differing extents, and induced the stabilisation or destabilisation of bilayers in a concentrationdependent manner. At certain concentrations, MRPs prevented the lamellar structure of bilayers from being destabilised by a viral fusion peptide, improved the lipid order and thereby inhibited cell-virus membrane fusion. The mechanism of the anti-influenza virus activity of RIE was therefore correlated to the interaction between MRPs and phospholipid bilayers, an integral component of the plasma membrane.