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dc.contributor.advisorCarroll, Anthony
dc.contributor.authorSenadeera, Dayani
dc.date.accessioned2018-03-09T07:22:08Z
dc.date.available2018-03-09T07:22:08Z
dc.date.issued2017-03
dc.identifier.doi10.25904/1912/3037
dc.identifier.urihttp://hdl.handle.net/10072/370991
dc.description.abstractThis thesis reports on the chemistry and anti-infective activity of the flowering plant family Myrtaceae (a family whose members dominate the Australian landscape). To understand the significance and importance of the Myrtaceae family from a phytochemical and medical perspective, a systematic literature review was carried out. The conclusion from this review was that the family is a major source of β-triketone, phloroglucinol, and volatile terpene natural products with the -triketones in particular being a major focus of recent research. Over hundred new compounds from this class, many of which possess novel ring systems, have been reported in the last ten years. Furthermore their chemical diversity is matched with their high biological activity, most notably anti-infective activities including antiplasmodial, antibacterial and antiviral being reported for these compounds. All the findings of the literature review are documented in Chapter 2 of this thesis. As a result of this review the experimental research carried out in this dissertation focused on the antiplasmodial and antibacterial activity of natural product constituents isolated from the flowers of three Australian Myrtaceae plant species, Corymbia intermedia, C. torelliana, and Angophora woodsiana collected from South East Queensland. These plants were chosen because of the literature precedent for Corymbia species to be a major source of bioactive - triketones and although Angophora species have not previously been investigated their close taxonomic relationship to the Corymbia suggested that they would likely be an additional source of -triketone constituents. A total of 24 β-triketone compounds, 14 of which are new, were isolated from methanol extracts of flowers of these three species. Structures of all the new and known compounds were elucidated using one-dimensional and two-dimensional NMR spectroscopy and mass spectrometry. The relative configurations of the stereogenic centres in the new compounds were assigned from detailed analysis of coupling constants in the 1H NMR spectra and correlations observed in ROESY spectra. Angophora woodsiana, a plant endemic to Australia yielded two new β-triketones, woodsianone A and woodsianone B and nine known β-triketones. (Chapter 5). The new compound, woodsianone A is only the third example of a β-triketone adduct containing a cadinene sesquiterpene. Woodsianone B is the first β-triketone epoxide derivative to be isolated from a natural source. Woodsianone B is an oxidation product of an olefin which has previously been proposed to be an intermediate in the biosynthesis of β-triketone-terpene adducts. This study was the first chemical investigation of any species from the genus Angophora and revealed that it is another Myrtaceae genus to contain β-triketones. Some of the known -triketones discovered in the flowers of Angophora woodsiana have previously been reported from other Corymbia species including C. ficifolia, and C. watsoniana, thus providing chemical evidence to support the morphological and molecular evidence for the close taxonomic relationship between the genus Angophora and Corymbia. Five new β-triketone/pinene adducts, intermediones A-E (Chapter 6) were isolated from Corymbia intermedia. Intermediones A-C, are C-6 phenyl analogs of 4S/4R-ficifolidione reported previously from C. ficifolia, while intermedione E is a structural isomer of intermedione A. The three compounds intermedione A-C are diastereomeric and detailed analysis of ROESY data was used to resolve their relative configurations. Intermedione D, an oxidized analogue of intermedione A posesses a novel oxadispiro[bicyclo[4.1.1]octane- 2,2'-furan-5',1''-cyclohexane tetracyclic ring system. The β-triketone chemistry of Corymbia intermedia was in agreement with previous chemical investigations of the genus and provided further evidence to substantiate the taxonomic differences between Corymbia and the genus Eucalytpus to which these species were previously assigned. Chemical investigation of the flowers of Corymbia torelliana yielded six new β-triketones, torellianones A-F, torellianol A and the four known β-triketones 4S/4R ficifolidiones, kunzeanone A and kunzeanone B (Chapter 7). Six of the new compounds, torellianones A-F, which are β-triketone/flavanone adducts, were isolated as inseparable diastereomeric mixtures. To further complicate the interpretation of 1D and 2D NMR data for torellianones E and F, each diastereomer was present as rotating mixture of conformations and this resulted in NMR spectra in which signals for four isomers were present. Despite this complexity the structures and relative configuration of the two diastereomers as well as the structures of each rotamer were determined from NMR analysis. A search of the literature revealed regioisomers of torellianones E and F had been reported earlier; however, the 1H NMR data previously reported was identical with that of the torellianones E and F. It was therefore concluded that the structures formerly reported was incorrect and has now been corrected. In addition, the published 1H and 13C NMR data for one of the known compounds, kunzeanone B, isolated previously from two Kunzea species was inconsistent with 1D and 2D NMR obtained in this study of C. torelliana and as a result the 1H and 13C NMR data for this compound have now been corrected. The fourth new compound, torellianol A is a 1,2,3,5- tetrahydroxycyclohexane and is likely to be reduced analog of a simple β-triketone. This structure class is rare and to date torrelianol A is the only fully reduced β-triketone to be reported in the literature. The isolated compounds were tested for antiplasmodial activity against the chloroquinesensitive 3D7 strains of Plasmodium falciparum. Compounds showing 5 M potency were also tested against the chloroquine resistant Dd2 strain of P. falciparum. Most of the compounds had IC50 values ranging from 1.5 μM - 15 μM. The most potent compounds were rhodomyrtone (IC50 1.8 ± 1.0 μM against the 3D7 strain) and woodsianone B (2.53 ± 0.11 μM against the Dd2 strain). The antibacterial activity of the isolated compounds was tested against Staphylococcus aureus ATCC 157293 and the most potent activity (MIC 0.02 mM) was reported from woodsianone B. The structure-activity relationship of the isolated β- triketones was assessed for antiplasmodial and antibacterial activities. It was identified that the β-triketone part of the molecules was essential for both activities. The poor water solubility demonstrated by some of the compounds suggests that synthetic modifications to increase their water solubility could lead to improved bioactivity.
dc.languageEnglish
dc.language.isoen
dc.publisherGriffith University
dc.publisher.placeBrisbane
dc.subject.keywordsAnti-infective compounds
dc.subject.keywordsMyrtaceae
dc.titleInvestigation of Anti-infective Compounds within the Flowers of Myrtaceae
dc.typeGriffith thesis
gro.facultyScience, Environment, Engineering and Technology
gro.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
gro.hasfulltextFull Text
dc.contributor.otheradvisorAvery, Vicky
gro.thesis.degreelevelThesis (PhD Doctorate)
gro.thesis.degreeprogramDoctor of Philosophy (PhD)
gro.departmentGriffith School of Environment
gro.griffith.authorSenadeera, Dayani


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