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    Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents

    Dolan, Niamh Anne (2013) Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents. PhD thesis, National University of Ireland Maynooth.

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    The European Centre for Disease Prevention and Control (ECDC) have estimated that on any given day 1 in 18 hospitalised patients have a healthcare-associated infection (HAI) and that a large percentage of these infections are caused by resistant strains of bacteria. With the global spread of antibiotic-resistance and the emergence of bacteria resistant to ‘last-resort antibiotics’, along with the lack of new classes of antibiotics being discovered, there is an urgent need for antibacterial research. Herein, three compound families were designed and synthesised in an effort to ascertain a compound with improved antibacterial activity. Each of the compounds synthesised were evaluated for their bacteriostatic activity against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and the Gram positive bacterium Staphylococcus aureus. A selection of the compounds were also evaluated for their in vivo toxicity using the larvae of the greater wax moth, Galleria mellonella. Firstly, a structure-activity relationship (SAR) study of a thiourea-based, bifuctional organocatalyst, which was found to exhibit bacteriostatic activity (MIC90 of 4.69- 6.25 g/mL against E. coli) comparable to that of vancomycin hydrochloride, was used to assess the structural components responsible for its activity. A number of structural features important for the overall activity of this compound were identified. Additionally, the hit compound and a selection of the SAR study compounds were also found to be non-toxic to the larvae of Galleria mellonalla. Secondly, modifications were made to the C-3 position of the well-known antibacterial quinolone structure. Two functionalities were chosen to replace the quinolone C-3 carboxylic acid, (1) the well-known carboxylic acid bioisostere, the (1H)-tetrazole, and (2) a hydroxamic acid. Both the (1H)-tetrazole and hydroxamic acid derivatives were found to exhibit bacteriostatic activity similar to that of their carboxylic acid analogues. Finally, the synthesis of a family of dioganotin(IV) dicarboxylates, including acetates, picolinates and nicotinates, as well as diorgantin(IV) dichlorides and their complexes with the ligands 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6- dione (dione) and dipyrido[3,2-a:2’,3’-c]phenazine (dppz) were also carried out. Of the compounds synthesised, the dibutyltin(IV) derivatives exhibited the broadest range of activity in comparison to the dimethyltin(IV) or diphenyltin(IV) derivatives. The addition of the picolinate or nicotinate group did not promote activity against any of the bacteria. Furthermore, only in the case of [Ph2SnCl2(dione)] was there improved activity compared to the organic ligand itself.

    Item Type: Thesis (PhD)
    Keywords: Design; Synthesis; Evaluation; Organic; Metal Based; Antimicrobial Agents;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7711
    Depositing User: IR eTheses
    Date Deposited: 10 Jan 2017 17:01
      Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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