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

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Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents Niamh Anne Dolan, B.Sc. A thesis submitted to the National University of Ireland Maynooth in accordance with the requirements for the Degree of Doctor of Philosophy in the Faculty of Science November 2013 Department of Chemistry NUI Maynooth Supervisors: Dr. John C. Stephens and Dr. John McGinley Head of Dept.: Dr. John C. Stephens Declaration of Authorship I hereby certify that the work presented within this thesis, except where acknowledged and cited, is my own work and has not been previously submitted for a Degree to this University or elsewhere. Niamh Anne Dolan National University of Ireland, Maynooth November 2013 II Acknowledgements Firstly, I would like to thank my supervisors, Dr. John C. Stephens and Dr. John McGinley. I thank you both for not only giving me the opportunity to carry out this research but also for your help and guidance throughout these last few years, your kind words, encouragement and support, thank you so much. Thank you to Prof. John Lowry and Dr. John C. Stephens for the opportunity to carry out this research at NUI Maynooth. I would also like to thank Dr. Kevin Kavanagh for giving me the opportunity to carry out all of my biological studies in the Medical Mycology laboratory at NUIM and for all of your advice and help. To all of the postgrads in the Medical Mycology lab, thank you for all of your help. It was always a pleasure to work in your lab. Thank you to Dr. Karen Thomkins, Dr. Alanna Smith and Niall Brown for your time and patience and all of your advice while teaching me the necessary techniques for the biological studies. A special thank you to Alanna for all of your help and advice, thank you so much. I would like to thank Dr. Bernadette S. Creaven and Dr. Ross Fitzgerald of ITT Dublin for your assistance with the 119Sn NMR spectroscopy. Thank you to Prof. Vickie McKee of Loughborough University for the X-ray crystallographic analysis. I would also like to thank all of the technicians at NUIM, Ken, Ria, Barbara, Ollie, Maryanne, Orla, and Anne for your help with everything from demonstrating to ordering chemicals and analysing my samples, thank you. A special thank you to Barbara for the multiple CHN and LC/TOF-MS analysis you have carried out for me and for all of your help and advice with HPLC, thank you very much. A big thank you, also, to Noel for looking after my laptop and for the many chats. To both the past and present members of my research groups, Dec, Rob, John M., Dean, Ross, Xin, Adam, John W., Denis, Niall, Laura, Ursula, Sam and Haixin for your help and your friendship. A special thank you to Dec, for your help and advice over the last few years, and to Rob, for the many chemistry chats and laughs. To Haixin, thank you so much for all of the papers. III I would also like to thank all of postgrads and postdocs in the Chemistry Department, for your help and for the many laughs. A special thank you to the girls from the biosensors lab, Keeley, Saidhbhe and Andy. Thank you for the many cups of tea, the many laughs and advice and for always lending an ear. Thank you also to the staff and lecturers of the NUIM chemistry department for your help and advice it was always very much appreciated. To Carol, Alanna and Trish. Thank you so much for your friendship over these last few years, for the many laughs, for listening, for your advice and continuous encouragement and support. I would’ve been lost without you. Thank you so much girls. It has been a pleasure to work with you all, and I wish you all the greatest success and happiness in your future work. To my parents, thank you for everything. I could not have come this far without you, your advice, your support, your endless encouragement and love. Thank you so much. To my sisters, Tina and Denise, for your endless support and encouragement, your advice, for your friendship and your love, thank you so much. I am very lucky to have been blessed with you as my family. To Joe, thank you for your love and understanding over these last few years. For the many trips and activities for helping me to de-stress. For your encouragement, advice and support, you made it all that little bit easier, thank you. IV Dedication To my parents Kathleen and Brian, with love. V 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 VI 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. VII Abbreviations Å Angstrom Alpha ADP Adenosine diphosphate A/E Attaching and effacing AcOH Acetic acid AI Autoinducer amu Atomic mass unit ATCC American Type Culture Collection ATP Adenosine triphosphate Beta bs Broad singlet BuLi Butyllithium oC Degrees Celsius ca. Circa CDC Centers for Disease Control and Prevention CF Cystic fibrosis CHN Carbon Hydrogen Nitrogen microanalysis Clf Clumping factor cm-1 Wavenumber Cna Collagen-binding protein CNF Cytotoxic necrotising factor VIII 13C NMR Carbon-13 Nuclear Magnetic Resonance COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate COSY Correlation spectroscopy CRE Carbapenem-resistant Enterobacteriaceae Delta d Doublet DCM Dichloromethane dd Doublet of doublets DIAD Diispropyl azidodicarboxylate DIEA N,N-diisopropylethylamine Dione 1,10-Phenanthroline-5,6-dione DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DNA Deoxyribonucleic acid Dppz Dipyrido[3,2-a:2’,3’-c]phenazine DPPA Diphenylphosphoryl azide EARS-Net European Antimicrobial Resistance Surveillence Network ECDC European Centre for Disease Prevention and Control ECDC-PPS European Centre for Disease Prevention and Control Point Prevalence Surveillence eEf Eukaryotic elongation factor EHEC Enterohaemorhagic Escherichia coli IX EPA Environmental Protection Agency EPEC Enteropathogenic Escherichia coli ESBL Extended--lactamase (ESBL) producing Escherichia coli EtCO2Cl Ethyl chloroformate Et3N Triethylamine Et3N.HCl Triethylammonium chloride Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol 19F NMR Fluorine-19 Nuclear Magnetic Resonance FBDD Fragment-based drug design Fnbp Fibrinogen-binding proteins Gamma g Gram(s) GI Gastrointestinal GSK GlaxoSmithKline h Hour(s) HAI Hospital-associated infection HCl Hydrochloric acid 1H NMR Proton Nuclear Magnetic Resonance H2O Water HOBt Hydroxybenzotriazole X HOMO Highest occupied molecular orbital HSQC Heteronuclear Single Quantum Correlation HTS High-throughput screening HUS Haemolytic Uraemic Syndrome Hz Hertz I Nuclear spin ID Inhibitory dose Ig Immunoglobulin IMO International maritime organisation IR Infra-red J Coupling constant KBr Potassium bromide K2CO3 Potassium carbonate Kg Kilogram KOH Potassium hydroxide L Litre LiAlH4 Lithium aluminium hydride LDA Lithium diisoproplyamide LTA Lipoteichoic acid LPS Lipopolysaccharide LUMO Lowest unoccupied molecular orbital M+ Parent molecular ion XI g Microgram M Micromolar MDR Multi-drug resistant Me Methyl MeCN Acetonitrile MeOH Methanol Me4Si Tetramethylsilane mg Milligram
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