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

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List of figures and schemes: Page Figure 1. 1 H-NMR spectrum for (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)…………………………5 Figure 2. 13 C-NMR spectrum for (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)………………………...5 Figure 3. ESI-MS spectrum for (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)………….………………6 Figure 4. Tandem ESI-MS 2 spectrum for (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)……..…………6 Figure 5. 1 H-NMR spectrum for (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)……………………….....6 Figure 6. 13 C-NMR spectrum for (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)……………………...…7 Figure 7. ESI-MS spectrum for (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)…………..……………....7 Figure 8. Tandem ESI-MS 2 spectrum for (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)…………..…….7 Figure 9. 1 H-NMR spectrum for (2R,3R)-2,3-dihydroxy dicarbohydrazide (5)………………..……………8 Figure 10. 13 C-NMR spectrum for (2R,3R)-2,3-dihydroxy dicarbohydrazide (5)………………..………….8 Figure 11. ESI-MS spectrum for (2R,3R)- 2,3-dihydroxy dicarbohydrazide (5)………….……….………..9 Figure 12. Tandem ESI-MS 2 spectrum for (2R,3R)-2,3-dihydroxy dicarbohydrazide (5)……….………….9 Scheme 1. Proposed fragmentation mechanism for (2R,3R)-2,3-dihydroxy dicarbohydrazide (5)….……....9 Figure 13. 1 H-NMR spectrum for (2S,3S)- 2,3-dihydroxy dicarbohydrazide (6)………………..………....10 Figure 14. 13 C-NMR spectrum for (2S,3S)- 2,3-dihydroxy dicarbohydrazide (6)………………..…….….10 Figure 15. ESI-MS spectrum for (2S,3S)-2,3-dihydroxy dicarbohydrazide (6)……………………..……..11 Figure 16. Tandem ESI-MS 2 spectrum for (2S,3S)- 2,3-dihydroxy dicarbohydrazide (6)……….….……..11 Scheme 2. Proposed fragmentation mechanism for (2S,3S)- 2,3-dihydroxy dicarbohydrazide (6)………..11 Optimisation of the [2+2]-cyclocondensation reaction • Figure 17. APCI-TOF MS for macrocycle 7 (ratio of hydrazide to dialdehyde is 2:1)...………..…12 • Figure 18. APCI-TOF MS for macrocycle 7 (ratio of hydrazide to dialdehyde is 1:2)…...….……12 • Figure 19. APCI-TOF MS for macrocycle 7 (ratio of hydrazide to dialdehyde is 1:1)…….……...13 • Figure 20. APCI-TOF MS for macrocycle 7 (ratio of hydrazide to dialdehyde is 1.2:1)…….……13 Figure 21. 1 H-NMR spectrum for macrocycle (7)………………………………………………………….14 Figure 22. ESI-MS spectrum for macrocycle (7)……………………...…………………………………...14 Figure 23. Tandem ESI-MS 2 spectrum for macrocycle (7)……..……………………..…………………...14 Figure 24. 1 H-NMR spectrum for macrocycle (8)………………………………………………………….15 Figure 25. ESI-MS spectrum for macrocycle (8)……………………...…………………………………...15 Figure 26. Tandem ESI-MS 2 spectrum for macrocycle (8)………..…………………...…………………..15 Scheme 3. Proposed fragmentation mechanism for macrocycle (8)………………………………………..16 Figure 27. APCI-MS 2 spectrum for macrocycle (9)………………………………………………………..16 Figure 28. APCI-MS 2 spectrum for macrocycle (9)………………………….…………………….……....17 Figure 29. 1 H-NMR spectrum for macrocycle (9)………………………………………………………….17 Figure 30. Tandem APCI-MS 2 spectrum for macrocycle (9)……..……….……………………………….17 S2
Scheme 4. Proposed fragmentation mechanism for macrocycle (9).…………………………………...…..18 Figure 31. Tandem ESI-MS 2 spectrum for macrocycle (9)……...………………………………..………...19 Scheme 5. Proposed fragmentation mechanism for macrocycle (9)……………..………………….……..19 Figure 32. 1 H-NMR spectrum for macrocycle (13)………………………………………………………...20 Figure 33. ESI-MS spectrum for macrocycle (13)……………………...………………………………….20 Figure 34. Tandem ESI-MS 2 spectrum for macrocycle (13)………...…………………..………………….20 Scheme 6. Proposed fragmentation mechanism macrocycle (13)………………………………….……....21 Figure 35. 1 H-NMR spectrum for macrocycle (14)………………………………………………………...21 Figure 36. ESI-MS spectrum for macrocycle (14)……………………...………………………………….22 Figure 37. Tandem ESI-MS 2 spectrum for macrocycle (14)………...…………………..………………….22 Scheme 7. Proposed fragmentation mechanism for macrocycle (14)…………………………..…………..22 Figure 38. 1 H-NMR spectrum for macrocycle (17)………………………………………………………...23 Figure 39. 1 H-NMR spectrum for macrocycle (17)………………………………...……………………....23 Figure 40. 1 H-NMR spectrum for macrocycle (17)……..………………...………………………………..24 Figure 41. APCI-MS 2 spectrum for macrocycle (17)……………………………………………………....24 Figure 42. APCI-MS 2 spectrum for macrocycle (17)………………………….…………………………...24 Figure 43. Tandem APCI-MS 2 spectrum for macrocycle (17)…………………………..………………...25 Scheme 8. Proposed fragmentation mechanism for macrocycle (17)………………………..……………..25 Figure 44. Tandem APCI-MS 2 spectrum for macrocycle (17)…………………………...………………..25 Scheme 9. Proposed fragmentation mechanism for macrocycle (17)……………………………..………..26 Figure 45. 1 H-NMR spectrum for macrocycle (10)………………………………………………………...26 Figure 46. ESI-MS spectrum for macrocycle (10)……….……………………………….………………..27 Figure 47. Tandem ESI-MS 2 spectrum for macrocycle (10)………….…………….………………..…….27 Figure 48. 1 H-NMR spectrum for macrocycle (11)………………………………………………………...27 Figure 49. APCI-MS spectrum for macrocycle (11)……………………………………….….…………...28 Figure 50. Tandem ESI-MS 2 spectrum for macrocycle (11)……………………………….………..…….28 Scheme 10. Proposed fragmentation mechanism for macrocycle (11)…………………………..………....29 Figure 51. APCI-MS 2 spectrum for macrocycle (12)……………………………………………………....29 Figure 52. Tandem APCI-MS 2 spectrum for macrocycle (12)……………………………….…………....30 Figure 53. 1 H-NMR spectrum for macrocycle (12)………………………………………………………...30 Figure 54. APCI-MS 2 spectrum for macrocycle (12)………………………………..……………………..30 Scheme 11. Proposed fragmentation mechanism for macrocycle (12)……………….……..……………...31 Figure 55. Tandem APCI-MS 2 spectrum for macrocycle (12)……………………………….…………….32 Scheme 12. Proposed fragmentation mechanism for macrocycle (12)……………….……..……………...32 Figure 56. 1 H-NMR spectrum for macrocycle (15)………………………………………………………...33 Figure 57. ESI-MS spectrum for macrocycle (15)….…………………………………….………………..33 Figure 58. Tandem ESI-MS 2 spectrum for macrocycle (15)……………………………………….………33 S3
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The Development of Novel Antibiotic
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Declaration of Authorship I, Hany N
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Abstract Over the past few decades,
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Chapter 2 Trianglimine Chemistry
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Figure 2.4 Trianglimines 10-12 with
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Abbreviations ACN AcOH Ala Acetonit
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RMS ROESY SjGST TFA THF TLC TMS TOC
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Introduction complete remodel of th
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Introduction following protonation.
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Introduction Lehn and co-workers re
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Introduction Figure 1.8 Generation
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Introduction Figure 1.11 Synthetic
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Introduction Figure 1.13 Generation
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Introduction 1.3.11 Boronic ester e
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Introduction References 1. E. Mouli
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Introduction 51. B. Shi, M. F. Grea
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Introduction Figure 2.2 shows compu
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Introduction incorporate β-cyclode
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Introduction Trianglamine-Zn(R) 2 c
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Introduction 24. J. Gajewy, J. Gawr
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Scope of Work Scope of Work In this
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Scope of Work can be obtained from
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Scope of Work Figure 3.4 Structures
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Scope of Work References 1. G. Wrig
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Organic & Biomolecular Chemistry Ci
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Downloaded by Jacobs University Bre
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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
Page 111 and 112: The polar carbamate group participa
Page 113 and 114: [2] WHO World health report 2003. h
Page 115 and 116: [32] B. Lienard, N. Selevsek, N. Ol
Page 117 and 118: FULL PAPER Synthesis and ESI-MS Com
Page 119 and 120: ability of the technique to provide
Page 121 and 122: aimed at assessing molecular recogn
Page 123 and 124: Paper 7 manuscript Synthesis, self-
Page 125 and 126: 2 Similar to the case of trianglimi
Page 127 and 128: 4 Receptor 7 showed enhanced recogn
Page 129 and 130: 6 The newly synthesized receptors s
Page 131 and 132: 8 27. Nour, H. F.; Hourani, N.; Kuh
Page 133 and 134: 120| P a g e Appendix
Page 135 and 136: Supplementary Information: Suppleme
Page 137 and 138: Supplementary Material (ESI) for Or
Page 153 and 154: Monitoring the [3+3]-cyclocondensat
Page 155 and 156: Monitoring the cyclocondensation re
Page 157 and 158: Product ions appeared as [M+H] + Fi
Page 159 and 160: Scheme 1. Assigned higher oligomers
Page 161: Supplementary Information: Synthesi
Page 165 and 166: DMSO Figure 1. 1 H-NMR spectrum for
Page 167 and 168: Figure 6. 13 C-NMR spectrum for (4S
Page 169 and 170: Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
Page 171 and 172: Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
Page 173 and 174: Intens. 4 x10 577.2 2.0 1.5 1.0 451
Page 175 and 176: HN N O O R R NH O O N N HN R O O O
Page 177 and 178: Intens. 5 x10 727.2 2.0 1.5 1.0 O O
Page 179 and 180: Intens. 5 x10 697.1 1.5 1.0 728.2 0
Page 181 and 182: O O O O HN N O O NH N HN N O O NH N
Page 183 and 184: Figure 38. 1 H-NMR spectrum for mac
Page 185 and 186: Intens. 5000 276.8 4000 3000 2000 1
Page 187 and 188: Intens. 7 x10 599.1 1.5 1.0 0.5 0.0
Page 189 and 190: (a) HN N O O NH O O N (b) HN N O NH
Page 191 and 192: Scheme 11. Proposed fragmentation m
Page 195 and 196: Scheme 14. Proposed fragmentation m
Page 197 and 198: Intens. 4 x10 550.9 3 2 1 0 500 100
Page 199 and 200: Figure 68. 2D-ROESY spectrum for ma
Page 201 and 202: Supplementary Information: Novel sy
Page 203 and 204: Intens. 6 x10 0.8 0.6 0.4 240.9 459
Page 205 and 206: Figure 9. 1 H-NMR spectrum for macr
Page 209 and 210: Intens. 5 x10 1.5 968.1 1.0 0.5 813
Page 211 and 212: Intens. 5 x10 897.4 4 2 335.3 707.3
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Scheme 3. Suggested fragmentation m
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Figure 35. 1 H-NMR spectrum for mac
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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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