An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Marcus Baumann and
Ian R. Baxendale

Review
Published 30 Oct 2013

596 Accesses

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1. Graphical Abstract
2. Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
  
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3. Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
  
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4. Scheme 3: Synthesis of 3-picoline and nicotinic acid.
  
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5. Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
  
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6. Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
  
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7. Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
  
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8. Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
  
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9. Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
  
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10. Scheme 8: Synthesis of rosiglitazone.
  
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11. Scheme 9: Syntheses of 2-pyridones.
  
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12. Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
  
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13. Scheme 11: Polymer-assisted synthesis of rosiglitazone.
  
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14. Scheme 12: Synthesis of pioglitazone.
  
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15. Scheme 13: Meerwein arylation reaction towards pioglitazone.
  
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16. Scheme 14: Route towards pioglitazone utilising tyrosine.
  
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17. Scheme 15: Route towards pioglitazone via Darzens ester formation.
  
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18. Scheme 16: Syntheses of the thiazolidinedione moiety.
  
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19. Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
  
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20. Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
  
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21. Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
  
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22. Scheme 19: Synthesis of moxifloxacin.
  
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23. Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
  
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24. Scheme 21: Synthesis of levofloxacin.
  
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25. Scheme 22: Alternative approach to the levofloxacin core 1.125.
  
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26. Figure 3: Structures of nifedipine, amlodipine and clevidipine.
  
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27. Scheme 23: Mg₃N₂-mediated synthesis of nifedipine.
  
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28. Scheme 24: Synthesis of rac-amlodipine as besylate salt.
  
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29. Scheme 25: Aza Diels–Alder approach towards amlodipine.
  
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30. Scheme 26: Routes towards clevidipine.
  
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31. Figure 4: Examples of piperidine containing drugs.
  
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32. Figure 5: Discovery of tiagabine based on early leads.
  
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33. Scheme 27: Synthetic sequences to tiagabine.
  
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34. Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
  
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35. Scheme 28: Enantioselective synthesis of solifenacin.
  
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36. Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
  
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37. Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
  
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38. Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
  
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39. Scheme 30: Improved route to carmegliptin.
  
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40. Figure 9: Structures of lamivudine and zidovudine.
  
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41. Scheme 31: Typical routes accessing uracil, thymine and cytosine.
  
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42. Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
  
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43. Scheme 33: Synthesis of lamivudine.
  
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44. Scheme 34: Synthesis of raltegravir.
  
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45. Scheme 35: Mechanistic studies on the formation of 3.22.
  
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46. Figure 10: Structures of selected pyrimidine containing drugs.
  
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47. Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
  
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48. Scheme 37: Synthesis of imatinib.
  
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49. Scheme 38: Flow synthesis of imatinib.
  
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50. Scheme 39: Syntheses of erlotinib.
  
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51. Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
  
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52. Scheme 41: Synthesis of lapatinib.
  
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53. Scheme 42: Synthesis of rosuvastatin.
  
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54. Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
  
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55. Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
  
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56. Scheme 44: Syntheses of varenicline and its key building block 4.5.
  
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57. Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
  
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58. Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
  
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59. Scheme 46: Asymmetric synthesis of bortezomib.
  
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60. Figure 13: Structures of some prominent piperazine containing drugs.
  
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61. Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
  
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62. Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  
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63. Scheme 48: Syntheses of azelastine (5.1).
  
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64. Figure 15: Structures of captopril, enalapril and cilazapril.
  
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65. Scheme 49: Synthesis of cilazapril.
  
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66. Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
  
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67. Scheme 50: Synthesis of lamotrigine.
  
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68. Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
  
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69. Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
  
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70. Scheme 52: Conventional synthesis of imiquimod (no yields reported).
  
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71. Scheme 53: Synthesis of imiquimod.
  
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72. Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
  
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73. Figure 18: Structures of various anti HIV-medications.
  
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74. Scheme 55: Synthesis of abacavir.
  
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75. Figure 19: Structures of diazepam compared to modern replacements.
  
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76. Scheme 56: Synthesis of ocinaplon.
  
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77. Scheme 57: Access to zaleplon and indiplon.
  
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78. Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
  
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79. Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
  
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80. Scheme 60: Early synthetic route to sildenafil.
  
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81. Scheme 61: Convergent preparations of sildenafil.
  
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82. Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
  
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83. Scheme 62: Short route to imidazotriazinones.
  
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84. Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
  
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85. Scheme 64: Bayer’s approach to the vardenafil core.
  
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86. Scheme 65: Large scale synthesis of vardenafil.
  
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87. Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
  
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88. Scheme 67: Different routes to temozolomide.
  
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89. Scheme 68: Safer route towards temozolomide.
  
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90. Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
  
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Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

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Polymer and small molecule mechanochemistry: closer than ever

José G. Hernández

Perspective
Published 14 Sep 2022

524 Accesses

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1. Graphical Abstract
2. Figure 1: Representation of (a) cavitation and elongational flow caused by pulsed ultrasonication, (b) mixer ...
  
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3. Scheme 1: (a) Mechanochemical activation of anthracene–endoperoxide mechanophore incorporated in the cross-li...
  
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4. Scheme 2: Mechanochemical activation of dendronized polymer-based compound 4 by ultrasonication and ball mill...
  
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5. Figure 2: Structure of cellulose and chitin and approximation to the structure of lignin.
  
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6. Figure 3: Tensile forces by ball milling change the conformation of a chitin model compound. This deformation...
  
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7. Figure 4: (a) Representation of a collision between the ball and a particle of a chitin sample and (b) mechan...
  
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8. Figure 5: (a) Ultrasound-induced ATRP using piezoelectric BaTiO₃ and (b) mechanochemical atom transfer radica...
  
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9. Figure 6: Mechanochemical solid-state complexation of organic capsule 5 with fullerenes C₇₀ in a planetary ba...
  
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10. Scheme 3: Comparative mechanochemical dissociation of the central C–C bond in TASN derivatives 6 and 8.
  
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Beilstein J. Org. Chem. 2022, 18, 1225–1235, doi:10.3762/bjoc.18.128

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Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

Karan Malhotra and
Jakob Franke

Review
Published 21 Sep 2022

484 Accesses

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1. Graphical Abstract
2. Figure 1: Enzyme function of cytochrome P450 monooxygenases (CYPs). A) Typical net reaction of CYPs, resultin...
  
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3. Figure 2: Phylogenetic distribution of CYPs acting on triterpenoid and steroid scaffolds (red nodes) compared...
  
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4. Figure 3: CYPs modifying steroid (A), cucurbitacin steroid (B) and tetracyclic triterpene (C) backbones. Subs...
  
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5. Figure 4: CYPs modifying pentacyclic 6-6-6-6-6 triterpenes. Substructures in grey indicate regions where majo...
  
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6. Figure 5: CYPs modifying pentacyclic 6-6-6-6-5 triterpenes (A) and unusual triterpenes (B). Substructures in ...
  
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7. Figure 6: Recent examples of multifunctional CYPs in triterpenoid and steroid metabolism in plants that insta...
  
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Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

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Thermally activated delayed fluorescence (TADF) emitters: sensing and boosting spin-flipping by aggregation

Ashish Kumar Mazumdar,
Gyana Prakash Nanda,
Nisha Yadav,
Upasana Deori,
Upasha Acharyya,
Bahadur Sk and
Pachaiyappan Rajamalli

Full Research Paper
Published 08 Sep 2022

412 Accesses

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1. Graphical Abstract
2. Scheme 1: Synthetic schemes of BPy-pTC and BPy-p3C.
  
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3. Figure 1: (a) Normalized absorption spectra of BPy-pTC and BPy-p3C in toluene at room temperature; (b) normal...
  
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4. Figure 2: Transient photoluminescence decay (λ_ex = 375 nm) of (a) BPy-pTC and (b) BPy-p3C in degassed THF (10...
  
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5. Figure 3: AIEE studies: Emission spectra (λ_ex = 375 nm, 10 µM) of (a) BPy-pTC and (d) BPy-p3C in THF with inc...
  
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6. Figure 4: Normalized fluorescence at room temperature and phosphorescence spectra at 77 K (λ_ex = 375 nm, 10 µ...
  
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7. Figure 5: Transient photoluminescence decay (λ_ex = 375 nm, 20 µM) of (a) BPy-pTC and (b) BPy-p3C aggregates i...
  
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8. Figure 6: Fluorescence switching by acid and base fumes exposure: Emission spectra (λ_ex = 375 nm) of (a) BPy-p...
  
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9. Figure 7: Fluorescence intensity vs number of exposures for (a) BPy-p3C and (b) BPy-pTC thin films upon expos...
  
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Beilstein J. Org. Chem. 2022, 18, 1177–1187, doi:10.3762/bjoc.18.122

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From amines to (form)amides: a simple and successful mechanochemical approach

Federico Casti,
Rita Mocci and
Andrea Porcheddu

Full Research Paper
Published 12 Sep 2022

351 Accesses

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

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Mechanochemical bottom-up synthesis of phosphorus-linked, heptazine-based carbon nitrides using sodium phosphide

Blaine G. Fiss,
Georgia Douglas,
Michael Ferguson,
Jorge Becerra,
Jesus Valdez,
Trong-On Do,
Tomislav Friščić and
Audrey Moores

Letter
Published 12 Sep 2022

346 Accesses

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1. Graphical Abstract
2. Scheme 1: a) Mechanochemical synthesis of g-PCN from sodium phosphide and trichlorotriazine (previous work [38]) ...
  
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3. Figure 1: PXRD patterns of g-h-PCN (green) and g-h-PCN300 (teal).
  
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4. Figure 2: XPS scans of a) C 1s, b) N 1s and c) P 2p for the pre-annealed g-h-PCN and d) C 1s, e) N 1s and f) ...
  
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5. Figure 3: ³¹P MAS NMR of a) g-h-PCN and b) g-h-PCN300. Asterisks denote spinning sidebands.
  
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6. Figure 4: Calculated structures for a) corrugated (edge facing), b) corrugated (single layer), c) layered g-h...
  
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Beilstein J. Org. Chem. 2022, 18, 1203–1209, doi:10.3762/bjoc.18.125

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Computational methods in drug discovery

Sumudu P. Leelananda and
Steffen Lindert

Review
Published 12 Dec 2016

334 Accesses

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1. Graphical Abstract
2. Figure 1: Schematic representation of a computer-aided drug discovery (CADD) pipeline. CADD methods are broad...
  
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3. Figure 2: FDA approved drugs Saquinavir and Amprenavir for the treatment of HIV infections. (a) The structure...
  
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4. Figure 3: (a) The crystal structure showing the binding of Dorzolamide (orange) to carbonic anhydrase II (pur...
  
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5. Figure 4: The best ligand binding site identified by SiteHound in HIV-1 protease. The ligand binding pocket i...
  
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6. Figure 5: Binding mode prediction. The known inhibitor Dorzolamide is docked into Carbonic anhydrase II cryst...
  
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7. Figure 6: The molecular structure of Raltegravir. Raltegravir is an FDA approved drug used in the treatment o...
  
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8. Figure 7: An example alchemical thermodynamic cycle for a protein–ligand binding free energy calculation. The...
  
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9. Figure 8: Schematic diagram showing the steps involved in QSAR. Known drug molecule activity and descriptor d...
  
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10. Figure 9: A few drugs discovered with the help of ligand-based drug discovery tools. (a) Zolmitriptan: used a...
  
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Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

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Antibiotics from predatory bacteria

Juliane Korp,
María S. Vela Gurovic and
Markus Nett

Review
Published 30 Mar 2016

333 Accesses

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1. Graphical Abstract
2. Figure 1: Natural products isolated from M. xanthus DK1622. DKxanthene-534 (1); myxalamid B (2); myxovirescin...
  
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3. Figure 2: Vegetative cells of P. fallax HKI 727 under a phase-contrast microscope (K. Martin, unpublished). B...
  
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4. Figure 3: Structures of myxopyronins A (11) and B (12), corallopyronins A (13), B (14) and C (15), as well as...
  
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5. Figure 4: Structure of althiomycin (17).
  
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6. Figure 5: Structures of cystobactamids 919-1 (18), 919-2 (19), and 507 (20).
  
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7. Figure 6: Structures of natural products isolated from Herpetosiphon spp.: siphonazole (21); auriculamide (22...
  
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Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

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Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

Péter Kisszékelyi,
Tibor Peňaška,
Klára Stankovianska,
Mária Mečiarová and
Radovan Šebesta

Full Research Paper
Published 09 Sep 2022

325 Accesses

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

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Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

Yan Sun,
Jing Sun and
Chao-Guo Yan

Full Research Paper
Published 03 Jan 2013

322 Accesses

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1. Graphical Abstract
2. Scheme 1: The four-component reactions containing dimedone (a) and cyclopentane-1,3-dione (b).
  
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3. Figure 1: Molecular structure of spiro[dihydropyridine-oxindole] 1b.
  
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4. Figure 2: The two kinds of spiro compounds from reactions of isatins with arylamines and cyclic 1,3-diketones....
  
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5. Figure 3: Molecular structure of spiro[dihydropyridine-oxindole] 2f.
  
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6. Scheme 2: Condensation reactions of isatins with cyclopentane-1,3-dione.
  
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7. Figure 4: Molecular structure of compound 3d.
  
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8. Scheme 3: Proposed reaction mechanism for the three-component reaction.
  
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Beilstein J. Org. Chem. 2013, 9, 8–14, doi:10.3762/bjoc.9.2

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An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Polymer and small molecule mechanochemistry: closer than ever

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

Thermally activated delayed fluorescence (TADF) emitters: sensing and boosting spin-flipping by aggregation

From amines to (form)amides: a simple and successful mechanochemical approach

Mechanochemical bottom-up synthesis of phosphorus-linked, heptazine-based carbon nitrides using sodium phosphide

Computational methods in drug discovery

Antibiotics from predatory bacteria

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

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