The Development of Novel Antibiotics Using ... - Jacobs University

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Contents Declaration of Authorship ……………………………………................................ iii Acknowledgements …………………………………….......................................... iv Abstract ……………………………………............................................................ v Contents ……………………………………............................................................ vi List of Figures …………………………………….................................................. viii Publications ……………………………………...................................................... x Abbreviations ……………………………………................................................... xi Introduction ……………………………………...................................................... 1 Chapter I ……………………………………..……………………………….. 1 1.1 Bacterial Resistance to Antibiotics ………………………………………... 1 1.2 Dynamic Combinatorial Chemistry ……………………….……………….. 2 1.3 Reversible Reactions Commonly Used in Generation of DCLs ………….... 3 1.3.1 Imine exchange …………………………………………………. 3 1.3.2 Hydrazone exchange ………………………………………….…….. 5 1.3.3 Disulfide exchange ……………………………………………… 7 1.3.4 Acetal exchange ……………………………………………….…….. 7 1.3.5 Thioester and ester exchange ………………………………………... 8 1.3.6 Pyrazolotriazinone metathesis …………………………………….… 9 1.3.7 Michael addition …………………………………….………………. 10 1.3.8 Alkene metathesis …………………………………………………… 11 1.3.9 Catalytic transamidation …………………………………………. 12 1.3.10 Thiazolidine exchange ………………………….………………….. 13 1.3.11 Boronic ester exchange ………………………….…………………. 14 1.3.12 Non-covalent exchange ………………………….…………………. 14 1.3.13 Metal-ligand non-covalent exchange ………………….…………… 15 1.3.14 Other reactions used in generation of DCLs ……………………….. 15 References ………………………………………………….……………… 16
Chapter 2 Trianglimine Chemistry ………………………………………………...... 19 2.1. Synthesis and conformational structure …….……………………………... 19 2.2. Applications of trianglimines ..…………………………………………….. 21 References ……………………………………………………………………… 25 Aim of Thesis ………………………………..……………………………………... 27 Scope of Work ……………………………………………………………………… 28 Paper 1 ……………………………………………………………………………………. 35 Paper 2 ……………………………………………………………………………………. 50 Paper 3 ……………………………………………………………………………………. 62 Paper 4 ……………………………………………………………………………………. 72 Paper 5 ……………………………………………………………………………………. 80 Paper 6 ……………………………………………………………………………………. 103 Paper 7 ……………………………………………………………………………………. 110 Conclusion ……….………………………………………………………………………. 119 Appendix …………………………………………………………………………………. 120 Letters of Permission ……………………………………………………………………... 273 Curriculum Vitae .……...…………………………………………………………………. 277
Page 1 and 2: The Development of Novel Antibiotic
Page 3 and 4: Declaration of Authorship I, Hany N
Page 5: Abstract Over the past few decades,
Page 9 and 10: Figure 2.4 Trianglimines 10-12 with
Page 11 and 12: Abbreviations ACN AcOH Ala Acetonit
Page 13 and 14: RMS ROESY SjGST TFA THF TLC TMS TOC
Page 15 and 16: Introduction complete remodel of th
Page 17 and 18: Introduction following protonation.
Page 19 and 20: Introduction Lehn and co-workers re
Page 21 and 22: Introduction Figure 1.8 Generation
Page 23 and 24: Introduction Figure 1.11 Synthetic
Page 25 and 26: Introduction Figure 1.13 Generation
Page 27 and 28: Introduction 1.3.11 Boronic ester e
Page 29 and 30: Introduction References 1. E. Mouli
Page 31 and 32: Introduction 51. B. Shi, M. F. Grea
Page 33 and 34: Introduction Figure 2.2 shows compu
Page 35 and 36: Introduction incorporate β-cyclode
Page 37 and 38: Introduction Trianglamine-Zn(R) 2 c
Page 39 and 40: Introduction 24. J. Gajewy, J. Gawr
Page 41 and 42: Scope of Work Scope of Work In this
Page 43 and 44: Scope of Work can be obtained from
Page 45 and 46: Scope of Work Figure 3.4 Structures
Page 47 and 48: Scope of Work References 1. G. Wrig
Page 49 and 50: Organic & Biomolecular Chemistry Ci
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View Online Downloaded by Jacobs Un
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Paper 2 Rapid Commun. Mass Spectrom
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Trianglimine formation mechanism by
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Paper 3 Org. Biomol. Chem., 2012, 1
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View Online Table 2 Distances (Å)
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Paper 4 Chem. Eur. J., 2012, submit
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(4R,5R)- and (4S,5S)-dimethyl-2,2-d
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that two distinct conformational is
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the thimble was recharged with fres
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Paper 5 Rapid Commu. Mass Spectrom.
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INTRODUCTION No single class of dru
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EXPERIMENTAL All the solvents and r
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(b) Refluxing macrocycles 5, 6 and
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Scheme 1. Graphical representation
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Figure 1. A plot of relative intens
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In contrast, formation of library m
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Figure 5. Generated dynamic library
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macrocycle 32 from the dynamic libr
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The polar carbamate group participa
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[2] WHO World health report 2003. h
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[32] B. Lienard, N. Selevsek, N. Ol
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FULL PAPER Synthesis and ESI-MS Com
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ability of the technique to provide
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aimed at assessing molecular recogn
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Paper 7 manuscript Synthesis, self-
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2 Similar to the case of trianglimi
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4 Receptor 7 showed enhanced recogn
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6 The newly synthesized receptors s
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8 27. Nour, H. F.; Hourani, N.; Kuh
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120| P a g e Appendix
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Supplementary Information: Suppleme
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Supplementary Material (ESI) for Or
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Monitoring the [3+3]-cyclocondensat
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Monitoring the cyclocondensation re
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Product ions appeared as [M+H] + Fi
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Scheme 1. Assigned higher oligomers
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Supplementary Information: Synthesi
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Scheme 4. Proposed fragmentation me
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DMSO Figure 1. 1 H-NMR spectrum for
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Figure 6. 13 C-NMR spectrum for (4S
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Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
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Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
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Intens. 4 x10 577.2 2.0 1.5 1.0 451
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HN N O O R R NH O O N N HN R O O O
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Intens. 5 x10 727.2 2.0 1.5 1.0 O O
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Intens. 5 x10 697.1 1.5 1.0 728.2 0
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O O O O HN N O O NH N HN N O O NH N
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Figure 38. 1 H-NMR spectrum for mac
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Intens. 5000 276.8 4000 3000 2000 1
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Intens. 7 x10 599.1 1.5 1.0 0.5 0.0
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(a) HN N O O NH O O N (b) HN N O NH
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Scheme 11. Proposed fragmentation m
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Scheme 14. Proposed fragmentation m
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Intens. 4 x10 550.9 3 2 1 0 500 100
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Figure 68. 2D-ROESY spectrum for ma
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Supplementary Information: Novel sy
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Intens. 6 x10 0.8 0.6 0.4 240.9 459
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Figure 9. 1 H-NMR spectrum for macr
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Page 209 and 210:
Intens. 5 x10 1.5 968.1 1.0 0.5 813
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Intens. 5 x10 897.4 4 2 335.3 707.3
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Scheme 3. Suggested fragmentation m
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Molecular modelling data for the co
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Figure 1. 1 H NMR spectrum for dica
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Intens. 2000 1493.6091 Host-Guest 1
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Intens. [%] 100 775.3 80 388.1 60 4
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Intens. 600 N HN O O 467.1916 400 O
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Intens. 6000 5000 HN N O O O O NH N
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Table 1. High resolution ESI-TOF da
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i Figure 1. 1 H NMR spectrum for ma
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i Figure 5. 1 H NMR spectrum for ma
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i j Figure 9. 1 H NMR spectrum for
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i Figure 13. DEPT-135 spectrum for
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Scheme 1. General mechanism of frag
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Intens. [%] 100 80 60 40 20 0 O H N
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Intens. [%] 100 1131.3 80 60 40 20
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Intens. 1500 1528.6088 1000 500 150
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Intens. [%] 100 80 60 40 Free guest
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Intens. 4 x10 1085.3575 1.25 1.00 0
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Intens. [%] 100 80 Free guest 586.1
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Synthesis, self-assembly and ESI-MS
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O O HN NH HN O O NH HN O 11 O NH O
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O O HN NH HN O O NH HN O 9 O NH O O
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H 2 O DMSO DMSO Figure 6. 1 H-NMR a
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Intens. 5 x10 5 -MS 487.1588 4 3 2
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Intens. -MS 6 x10 0.8 0.6 0.4 0.2 1
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Intens. -MS 6 x10 O O 350.9 1.5 1.0
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Intens. [%] 100 -MS 486.9 Exact str
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Intens. [%] -MS 100 486.9 80 60 975
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Intens. [%] +MS 100 80 517.2 Exact
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Intens. [%] 100 80 60 +MS 388.1 775
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 80 +MS 1031.4939 7
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 -MS 2 586.1 80 60 4
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Intens. [%] 100 -MS 2 875.2 Exact s
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Table 1. High resolution ESI-TOF/MS
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274 | P a g e
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276 | P a g e
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4. H. Nour, A. López-Periago, N. K
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