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Development of Novel Antibacterial Agents Through the Design and Synthesis of Aminoacyl Trna Synthetase (Aars) Inhibitors

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Development of Novel Antibacterial Agents Through the Design and Synthesis of Aminoacyl Trna Synthetase (Aars) Inhibitors Medicinal Chemistry Division, Cardiff school of Pharmacy and Pharmaceutical Sciences, Cardiff University Development of Novel Antibacterial Agents through the Design and Synthesis of Aminoacyl tRNA Synthetase (AaRS) Inhibitors A thesis submitted in accordance with the conditions governing candidates for the degree of Philosophiae Doctor in Cardiff University Hanadi Asiri Supervisors: Dr. Claire Simons Dr. Efi Mantzourani December 2020 Acknowledgements Thanks God Almighty for good health, peace of mind and the strength to finish this research despite the difficult situations. Thanks God, for giving me chance to know Dr. Claire Simons. I would like to express my sincere gratitude to my supervisor Dr. Claire Simons for her continuous support, guidance, teaching, patience, enthusiasm and endless helping throughout my PhD journey. The completion of this thesis could not have been possible without her valuable experience. I would like to thank Dr. Efi Mantzourani for her support and valuable advice throughout the course of this research. Thanks to the EPSRC mass spectrometry service centre, Shaun Reeksting from Bath University and Medac Ltd. for the accurate mass, HPLC measurements and the microanalysis determination. A Big thank to Jennifer Richard, Dr. Mandy Wootton, Casey Hughes and Dr. James Bullard for the antimicrobial screening test and aminoacylation assay results. Finally, many thanks to all the members in Cardiff University who help and encourage me and do not forget to thank my mum (Aminah Al-Anbar), sisters (Al-Anoud and Alaa Asiri), brother (Abdullah Asiri), children (Amal, Yaser, Yazen and Nouf) and my husband (Musaad Al-Makhilib) for their unconditional support, love and encouragement. iii In the name of God, most gracious, most Merciful This thesis is dedicated to my supervisor (Claire Simons) for her support Read! In the Name of your Lord who has created ❶ He has created man from a clot ❷ Read! And your Lord is the most Generous ❸ Who has taught (the writing) by the pen ❹ He has taught man that which he knew not ❺ Nay! Verily, man does transgress (in disbelief and evil deed) ❻ Because he considers himself self-sufficient ❼ Surely, to your Lord is the return❽ Surah Al-Alag (The Clot) (96) iv Abstract Antimicrobial resistance is a global public health issue which significantly threatens human life. There are approximately 50,000 deaths in the USA and Europe per year owing to antimicrobial resistance infections. This burden of resistance has increased resulting in an increase in morbidity and mortality in clinical and community setting. Thus, global collaborative action is needed for developing effective strategies to combat antimicrobial resistance. International and local approaches including antimicrobial surveillance, guidelines for treatment of bacterial infections, regulation of the availability of antibiotics, improving hand hygiene, understanding the mechanism of bacterial resistance and development of new antimicrobial agents have been advised. Aminoacyl tRNA synthetases are valuable targets for antibiotic development as they have a fundamental role at a cellular level during the translation process of the genetic code. Mupirocin (Bactroban ®) is an approved isoleucine tRNA synthetase inhibitor which is used for the treatment of methicillin resistant Staphylococcus aureus (MRSA). High and low level of mupirocin resistance has been demonstrated in most S. aureus isolates due to acquired plasmid-mediated mupA, which encodes a novel IleRS and mutation, respectively. Thus, the design of multitarget aminoacyl tRNA synthetases inhibitors could be an effective way to make significant reductions in the biological fitness of bacteria leading to a reduction in drug resistant microorganisms. Class IIb aminoacyl tRNA synthetases of which AspRS and AsnRS belong is a target of the project in Staphylococcus aureus and Enterococcus faecalis. A computational study of both enzymes in both microorganisms including homology modelling, validation techniques, molecular dynamics and docking of the natural substrates (aa-AMP) were used to be a platform for the design of dual site inhibitors containing a sulphamoyl linkage which mimic aa-AMP in both enzymes. Different series of AspRS/AsnRS inhibitors were designed to occupy both pockets of the target enzymes then synthesised after optimisation their synthetic routes. The minimum inhibitory concentration of compounds against a panel of microorganisms were evaluated compared with ciprofloxacin as the standard and one compound showed good inhibitory activity against Enterococcus faecalis (MIC = 2 µg/mL). v Content Content No. Chapter 1 1 1. Introduction 2 1.1. Antimicrobial resistance (AMR) 2 1.2. Mechanism of bacterial resistance 4 1.3. Gram positive bacteria 8 1.3.1. Staphylococcus aureus 9 1.3.1.1. Structure of Staphylococcus aureus 9 1.3.1.2. Methicillin resistant Staphylococcus aureus (MRSA) 10 1.3.1.3. Diseases related to Staphylococcus aureus 11 1.3.1.3.1. Staphylococcus aureus bacteraemia (SAB) 11 1.3.1.3.2. Infective endocarditis 12 1.3.1.3.3. Pleuropulmonary infection 12 1.3.1.3.4. Skin and soft tissue infection 12 1.3.1.3.5. Osteoarticular infection 13 1.3.2. Enterococcus faecalis 14 1.3.2.1. Resistance in Enterococcus faecalis 14 1.4. Aminoacyl tRNA synthetases 15 1.4.1. Classification of aminoacyl tRNA synthetases 17 1.4.2. Aminoacylation proofreading 24 1.4.3. Indirect pathway of aminoacylation 25 1.4.4. Other functions of aminoacyl tRNA synthetases 25 1.4.5. Aminoacyl tRNA synthetases inhibitors 27 1.5. Aim and objectives 36 Chapter 2 37 2. Introduction 38 2.1. Staphylococcus aureus aminoacyl tRNA synthetases 41 2.1.1. Class I S. aureus aminoacyl tRNA synthetases 41 2.1.2. Class II S. aureus aminoacyl tRNA synthetases 42 2.2. Enterococcus faecalis aminoacyl tRNA synthetases 46 2.2.1. Class I E. faecalis aminoacyl tRNA synthetases 46 2.2.2. Class II E. faecalis aminoacyl tRNA synthetases 47 2.3. Result and discussion 51 2.3.1. Computational analysis of S. aureus aminoacyl tRNA synthetases 51 2.3.1.1. Construction of S. aureus AspRS and AsnRS models 52 2.3.1.1.1. Homology search of S. aureus AspRS and AsnRS 52 2.3.1.2. Multiple sequence and structure alignment 56 2.3.1.3. 3D S. aureus AspRS and AsnRS models building and validation 60 2.3.1.4. Docking study of S. aureus AspRS and AsnRS models 72 2.3.1.4.1. Active site identification 72 2.3.1.4.2. Metal binding 78 2.3.1.5. Molecular dynamic of S. aureus AspRS and AsnRS models 81 2.3.1.6. Final constructed S. aureus AspRS and AsnRS models 85 2.3.2. Computational analysis of E. faecalis aminoacyl tRNA synthetases 88 2.3.2.1. Construction of E. faecalis AspRS and AsnRS models 89 2.3.2.1.1. Homology search of E. faecalis AspRS and AsnRS 89 vi 2.3.2.1.2. Multiple sequence and structure alignment 93 2.3.2.1.3. 3D E. faecalis AspRS and AsnRS models building and validation 97 2.3.2.1.4. Docking study of E. faecalis AspRS and AsnRS models 109 2.3.2.1.4.1. Active site identification 109 2.3.2.1.4.2. Metal binding 114 2.3.2.1.5. Molecular dynamic of E. faecalis AspRS and AsnRS models 117 2.2.2.1.6. Final constructed E. faecalis AspRS and AsnRS models 121 2.4. Selectivity study of S. aureus and E. faecalis AspRS and AsnRS with their 123 human counterparts 2.5. Methods 126 2.5.1. Homology search 126 2.5.2. Multiple sequence and structure alignment 126 2.5.3. 3D model building 127 2.5.4. Model validation 127 2.5.5. Docking study 128 2.5.6. Molecular dynamic 128 2.5.7. Binding affinity (ΔG) calculations 128 Chapter 3 130 3. Introduction 131 3.1. Synthetic pathway for sulphonyl piperazinyl methanone derivatives 133 (7, 10 and 14) 3.1.1. Synthesis of sulfonyl piperazine derivatives (3a-f) 136 3.1.2. Synthesis of acid chlorides (6 and 9) 138 3.1.3. Synthesis of sulfonyl piperazinyl methanone derivatives (7a-f, 10a-d 139 and 14a-d) 3.2. Docking studies 142 3.2.1. Docking studies of S. aureus AspRS 142 3.2.2. Docking studies of S. aureus AsnRS 148 3.2.3. Docking studies of E. faecalis AspRS 154 3.2.4. Docking studies of E. faecalis AsnRS 159 3.3. Molecular dynamic studies 165 3.4. Biological assays 169 3.4.1. Microbiological screening 169 3.4.2. Aminoacylation assay 175 3.5. Methods 178 3.5.1. Docking and molecular dynamic studies 178 3.5.2. Biological assay 178 3.5.2.1. Antimicrobial screening test 178 3.5.2.2. Aminoacylation assay 179 3.5.3. Chemistry 179 3.5.3.1. General procedure for the preparation of phenyl sulfonyl 180 piperazines (3a-f) (329) 3.5.3.1.1. 1-Tosyl piperazine (3a) 181 3.5.3.1.2. 1-((4-Nitrophenyl)sulfonyl)piperazine (3b) 181 3.5.3.1.3. 1-([1,1'-Biphenyl]-4-yl)sulfonyl)piperazine (3c) 181 3.5.3.1.4. 1-((4’-Methoxy-[1,1’-biphenyl]-4-yl)sulfonyl)piperazine (3d) 181 3.5.3.1.5. 1-((4'-Fluoro-[1,1'-biphenyl]-4-yl)sulfonyl)piperazine (3e) 182 vii 3.5.3.1.6. 1-((4'-Chloro-[1,1'-biphenyl]-4-yl)sulfonyl)piperazine (3f) 182 3.5.3.2. General procedure for the preparation of acid chlorides (6 and 9) 182 3.5.3.2.1. 5-Methylisoxazole-4-carbonyl chloride (6) 183 3.5.3.2.2. 4-Methylthiazole-5-carbonyl chloride (9) 183 3.5.3.3. General procedure for the preparation of (5-methylisoxazol-4-yl)(4- 183 ((4-phenyl)sulfonyl)piperazin-1-yl)methanone derivatives (7a-f) and (4- methylthiazol-5-yl)(4-((4-phenyl)sulfonyl)piperazin-1-yl)methanone derivatives (10a-d).
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