Studies on biologically active natural products and synthesis of fluorinated heterocyclic drug scaffolds using SNAr substitution reactions
thesisposted on 10.09.2018 by Amira Khalaf-H-N-Al-Jabiry
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Natural products were and still represent novel science to be investigated for drug discovery and design. This work involved extraction and analysis of natural products from durian and bitter apple, two fruits which still have not been properly explored, especially the bitter apple fruit from the Qatar desert (Citrullus colocynthis). Mass spectrometric and NMR spectroscopic results have indicated promising compounds are present in the fruits. Extracts were found to exhibit anti-oxidant and anti-microbial activity. A range of chromatographic separation techniques were employed to try to separate and identify active compounds, but the complexity of the mixtures extracted has did not allow identification of individual compounds. Anti-microbial activity was observed against Escherichia coli and Staphylococcus epidermidis and anti-oxidant activity was investigated by two in vitro methods, a DPPH free radical scavenging assay and the Folin–Ciocalteu phenolics assay. The most potent activity was found to be from skin extracts of the bitter apple Citrullus colocynthis against Staphylococcus epidermidis based on the disc-diffusion method. A second part of the project involved synthesis of sulfur containing compounds of interest as hydrogen sulfide (H2S) generating molecules of application in the study of H2S-signalling pathways, and with potential as antibiotic agents. Synthesis of a range of amino acid derived phosphorothioamidates was investigated. Compounds were successfully prepared and characterised by 1H and 31P NMR spectroscopy, but were found to be rather labile compounds with limited stability. In a further aspect of the synthetic work, a series of polyfluorinated heterocycles were prepared. Reaction of perfluoroarenes with ortho-amidobenzenethiols was studied which led to formation of fluorinated phenothiazine derivatives. An unexpected Smiles rearrangement occurred during the cyclisation reaction, in which the initially formed sulfide link was broken by base catalysed attack of the amido group forming an aryl amide connection to the fluoroarene. The liberated thiolate then effected cyclisation by SNAr reaction at the 3-position of the fluoroarene generating phenothiazines with reversed ring fusion to that initially expected. Fourteen new novel compounds were prepared successfully and characterised by NMR, IR and mass spectrometry, three of which were successfully crystallised, and the structures of these three compounds were confirmed by X-ray crystallography. Study of the reaction of perfluoroarenes with 2-aminobenylamine was also undertaken with the hope of forming fluorinated benzo-fused diazepine derivatives. The primary amine group was found to successfully bond to the fluoroarenes through SNAr reaction, but cyclisation did not occur readily, possibly to the difficulty of closing the larger seven-membered ring. Tentative mass spectrometric evidence was obtained when pentafluorobenzonitrile was employed as substrate suggesting a trace amount of the cyclisation product had been formed indicating further work would be desirable in this area.
Qatar Foundation for Education, Science and Community Development