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Title: Attempts to synthesise substituted quinolones as antibiotic targets using solid phase techniques
Author: Bakhotmah, Dina Abed
Awarding Body: University of Sunderland
Current Institution: University of Sunderland
Date of Award: 2013
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Quinolones, and especially fluoroquinolones, are one of the largest classes of antibacterial agents used worldwide. Thus, the risk of emerging resistance and toxicity increases the need for new and improved agents and synthesis methodologies. Solid phase organic synthesis has become an important technique in drug design. This research aimed to establish the advantages of solid phase syntheses in the preparation of fluoroquinolones antibacterial agents. In the present investigation, several trials using both solution and solid phase syntheses were attempted for the preparation of fluoroquinolones using the Vilsmeier reaction. Merrifield resin and p-nitrophenyl carbonate Wang resin were used in the solid phase synthesis. A number of fluoro- and non-fluoro compounds were investigated, along with a wide range of catalysts and conditions. The Vilsmeier approach had limited applicability in quinolone synthesis. On the other hand, the Vilsmeier reaction with oxalyl chloride produced a dimer product (bis-amide). Instead of the desired target quinolone product, we identified two bis-fluoroinated derivatives, N,N'-bis-(4-fluoro- 3-nitrophenyl) oxalamide and N,N'-bis-(3-chloro-4-fluorophenyl) malonamide in solution phase. Recently, Sechi et al (2008) reported an analogous non-fluorinated dimer product as a potential HIV-1 integrated inhibitor. Elemental analysis, mass spectrometry (MS), Fourier transform infra red spectroscopy (FT-IR), 'H and 13C nuclear magnetic resonance spectroscopy (NMR) and heteronuclear multiple quantum correlation (HMQC) were used to identify the structures of all newly synthesised compounds. Biological evaluation for the selected 12 compounds synthesised in this study showed a significant biocidal effect over the standard nystain and nalidixic acid. The relationships between the bioactive effects minimum inhibitory concentration (MIC), physicochemical parameters includes, partition coefficient, thermal behaviour, melting point, solubility and FT-IR spectroscopy have been investigated. The 7-bromoquinolone analogue, 7-bromo-6-(N-benzylpiperazin-1-yl)-4-oxo-3- quinolone carboxylic acid 91 showed the high potency as antibacterial inhibitor in addition to a significant effect on vitiligo phototherapy treatment. In addition, quinolone derivative analogues were synthesised and investigated as amylolytic agents towards some Aspergillus fungi.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available