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