Recent Advances in the Synthesis and Biological Activity of Pyrrolo[2,3-c]pyridines

Authors

  • Volodymyr V. Voloshchuk Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd., Ukraine http://orcid.org/0009-0001-9403-0176
  • Sergey P. Ivonin Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.24.303972

Keywords:

pyrrolo[2,3-c]pyridines, 6-azaindoles, prediction of biological activity, medicinal chemistry, heterocyclic compounds, drug development

Abstract

Pyrrolo[2,3-c]pyridines (6-azaindoles) are the most promising nitrogen-containing heterocyclic compounds in the field of drug development. Exhibiting extraordinary versatility as pharmacophores, they are widely used in the development of kinase inhibitors, antiproliferative agents, and as potential therapeutic agents for the treatment of various diseases, including cancer and Alzheimer’s disease. A large number of works focusing on new methods and approaches in the synthesis of 6-azaindoes, as well as on the study of their biological activity, have been published worldwide. In our review, we tried to classify all currently known strategies for the construction of the 6-azaindole core, which were published within the last 15 years, the chemical diversity of the derivatives obtained, and their therapeutic potential in the context of medicinal chemistry. We hope that this work will generalize and facilitate the understanding of the strategy for the synthesis of pyrrolo[2,3-c]pyridines, as well as help scientists in their further research in the direction of 6-azaindoles.

Supporting Agency

  • The authors received no specific funding for this work.

Downloads

Download data is not yet available.

References

  1. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57 (22), 10257–10274. https://doi.org/10.1021/jm501100b.
    | |
  2. Popowycz, F.; Mérour, J.-Y.; Joseph, B. Synthesis and Reactivity of 4-, 5- and 6-azaindoles. Tetrahedron 2007, 63 (36), 8689–8707. https://doi.org/10.1016/j.tet.2007.05.078.
    |
  3. Blaazer, A. R.; Lange, J. H. M.; van der Neut, M. A. W.; Mulder, A.; den Boon, F. S.; Werkman, T. R.; Kruse, C. G.; Wadman, W. J. Novel Indole and Azaindole (Pyrrolopyridine) Cannabinoid (CB) Receptor Agonists: Design, Synthesis, Structure-Activity Relationships, Physicochemical Properties and Biological Activity. Eur. J. Med. Chem. 2011, 46 (10), 5086–5098. https://doi.org/10.1016/j.ejmech.2011.08.021.
    | |
  4. Ganser, C.; Lauermann, E.; Maderer, A.; Stauder, T.; Kramb, J.-P.; Plutizki, S.; Kindler, T.; Moehler, M.; Dannhardt, G. Novel 3‑Azaindolyl-4-arylmaleimides Exhibiting Potent Antiangiogenic Efficacy, Protein Kinase Inhibition, and Antiproliferative Activity. J. Med. Chem. 2012, 55 (22), 9531–9540. https://doi.org/10.1021/jm301217c.
    | |
  5. Lee, H.-Y.; Tsai, A.-C.; Chen, M.-C.; Shen, P.-J.; Cheng, Y.-C.; Kuo, C.-C.; Pan, S.-L.; Liu, Y.-M.; Liu, J.-F.; Yeh, T.-K.; Wang, J.-C.; Chang, C.-Y.; Chang, J.-Y.; Liou, J.-P. Azaindolylsulfonamides, with a More Selective Inhibitory Effect on Histone Deacetylase 6 Activity, Exhibit Antitumor Activity in Colorectal Cancer HCT116 Cells. J. Med. Chem. 2014, 57 (10), 4009–4022. https://doi.org/10.1021/jm401899x.
    | |
  6. Meuser, M. E.; Rashad, A. A.; Ozorowski, G.; Dick, A.; Ward, A. B.; Cocklin, S. Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor. Molecules 2019, 24 (8), 1581. https://doi.org/10.3390/molecules24081581.
    | |
  7. Carbone, A.; Parrino, B.; Di Vita, G.; Attanzio, A.; Spanò, V.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Livrea, M. A.; Diana, P.; Cirrincione, G. Synthesis and Antiproliferative Activity of Thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, Nortopsentin Analogues. Mar. Drugs 2015, 13(1), 460-492. https://doi.org/10.3390/md13010460.
    | |
  8. Plewe, M. B.; Butler, S. L.; Dress, K. R.; Hu, Q.; Johnson, T. W.; Kuehler, J. E.; Kuki, A.; Lam, H.; Liu, W.; Nowlin, D.; Peng, Q.; Rahavendran, S. V.; Tanis, S. P.; Tran, K. T.; Wang, H.; Yang, A.; Zhang, J. Azaindole Hydroxamic Acids are Potent HIV-1 Integrase Inhibitors. J. Med. Chem. 2009, 52 (22), 7211–7219. https://doi.org/10.1021/jm900862n.
    | |
  9. Crawford, T. D.; Tsui, V.; Flynn, E. M.; Wang, S.; Taylor, A. M.; Côté, A.; Audia, J. E.; Beresini, M. H.; Burdick, D. J.; Cummings, R. T.; Dakin, L. A.; Duplessis, M.; Good, A. C.; Hewitt, M. C.; Huang, H.-R.; Jayaram, H.; Kiefer, J. R.; Jiang, Y.; Murray, J. M.; Nasveschuk, C. G.; Pardo, E.; Poy, F.; Romero, F. A.; Tang, Y.; Wang, J.; Xu, Z.; Zawadzke, L. E.; Zhu, X.; Albrecht, B. K.; Magnuson, S. R.; Bellon, S. F.; Cochran, A. G. Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains. J. Med. Chem. 2016, 59 (11), 5391–5402. https://doi.org/10.1021/acs.jmedchem.6b00264.
    | |
  10. Dimitrakis, S.; Gavriil, E.-S.; Pousias, A.; Lougiakis, N.; Marakos, P.; Pouli, N.; Gioti, K.; Tenta, R. Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation. Molecules 2022, 27 (1), 247. https://doi.org/10.3390/molecules27010247.
    | |
  11. 11. Lougiakis, N.; Sakalis, N.; Georgiou, M.; Marakos, P.; Pouli, N.; Skaltsounis, A.-L.; Mavrogonatou, E.; Pratsinis, H.; Kletsas, D. Synthesis, cytotoxic activity evaluation and mechanistic investigation of novel 3,7-diarylsubstituted 6-azaindoles. Eur. J. Med. Chem. 2023, 261, 115804. https://doi.org/10.1016/j.ejmech.2023.115804.
    | |
  12. McDaniel, K. F.; Wang, L.; Soltwedel, T.; Fidanze, S. D.; Hasvold, L. A.; Liu, D.; Mantei, R. A.; Pratt, J. K.; Sheppard, G. S.; Bui, M. H.; Faivre, E. J.; Huang, X.; Li, L.; Lin, X.; Wang, R.; Warder, S. E.; Wilcox, D.; Albert, D. H.; Magoc, T. J.; Rajaraman, G.; Park, C. H.; Hutchins, C. W.; Shen, J. W.; Edalji, R. P.; Sun, C. C.; Martin, R.; Gao, W.; Wong, S.; Fang, G.; Elmore, S. W.; Shen, Y.; Kati, W. M. Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor. J. Med. Chem. 2017, 60 (20), 8369–8384. https://doi.org/10.1021/acs.jmedchem.7b00746.
    | |
  13. Linz, S.; Müller, J.; Hübner, H.; Gmeiner, P.; Troschütz, R. Design, synthesis and dopamine D4 receptor binding activities of new N-heteroaromatic 5/6-ring Mannich bases. Bioorg. Med. Chem. 2009, 17 (13), 4448-4458. https://doi.org/10.1016/j.bmc.2009.05.015
    | |
  14. Arikawa, Y.; Hasuoka, A.; Hirase, K.; Inatomi, N.; Sato, F.; Hori, Y.; Takagi, T.; Tarui, N.; Kawamoto, M.; Kajino, M. Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers. Chem. Pharm. Bull. 2014, 62 (4), 336–342. https://doi.org/10.1248/cpb.c13-00878.
    | |
  15. McDonald, I. M.; Mate, R.; Ng, A.; Park, H.; Olson, R. E. Novel Tricyclic Diamines 2. Synthesis of 1,7-Diazaisoadamantane, 1,5-Diazaisoadamantane and 1,6-Diazahomobrendane. Tetrahedron Lett. 2018, 59, 751–754. https://doi.org/10.1016/j.tetlet.2018.01.028.
    |
  16. Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.; Senanayake, C. H. A Novel One-Step Synthesis of 2-Substituted 6-Azaindoles from 3-Amino-4-Picoline and Carboxylic Esters. J. Org. Chem. 2005, 70 (16), 6512–6514. https://doi.org/10.1021/jo0506480.
    | |
  17. Fang, Y.-Q.; Yuen, J.; Lautens, M. A General Modular Method of Azaindole and Thienopyrrole Synthesis Via Pd-Catalyzed Tandem Couplings of gem-Dichloroolefins. J. Org. Chem. 2007, 72 (14), 5152–5160. https://doi.org/10.1021/jo070460b.
    | |
  18. Gorugantula, S. P.; Carrero-Martínez, G. M.; Dantale, S. W.; Söderberg, B. C. G. Palladium-Catalyzed Reductive N-Heterocyclization of Alkenyl-Substituted Nitroarenes as a Viable Method for the Preparation of Bicyclic Pyrrolo-Fused Heteroaromatic Compounds. Tetrahedron 2010, 66 (10), 1800–1805. https://doi.org/10.1016/j.tet.2010.01.029.
    |
  19. Formenti, D.; Ferretti, F.; Ragaini, F. Synthesis of N-Heterocycles by Reductive Cyclization of Nitro Compounds Using Formate Esters as CO Surrogates. ChemCatChem 2018, 10 (1), 148–152. https://doi.org/10.1002/cctc.201701214.
    |
  20. Son, N. T.; Nguyen, T. A.; Blanco, M.; Ehlers, P.; Thuan, N. T.; Dang, T. T.; Langer, P. Synthesis of 5- and 6-Azaindoles by Sequential Site-Selective Palladium-Catalyzed C–C and C–N Coupling Reactions. Synlett 2020, 31 (13), 1308–1312. https://doi.org/10.1055/s-0040-1707853.
    |
  21. Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; Lü, Z.; Zhang, L.; Jia, Y. Palladium-Catalyzed Indole and Azaindole Synthesis by Direct Annulation of Electron-Poor o-Chloroanilines and o-Chloroaminopyridines with Aldehydes. Synthesis 2008, 24, 3981–3987. https://doi.org/10.1055/s-0028-1083225.
    |
  22. Jeanty, M.; Blu, J.; Suzenet, F.; Guillaumet, G. Synthesis of 4- and 6-Azaindoles via the Fischer Reaction. Org. Lett. 2009, 11 (22), 5142–5145. https://doi.org/10.1021/ol902139r.
    | |
  23. Parrino, B.; Spanò, V.; Carbone, A.; Barraja, P.; Diana, P.; Cirrincione, G.; Montalbano, A. Synthesis of the New Ring System Bispyrido[4',3':4,5]pyrrolo[1,2-a:1',2'-d]pyrazine and Its Deaza Analogue. Molecules 2014, 19 (9), 13342–13357. https://doi.org/10.3390/molecules190913342.
    | |
  24. Zhang, J.; Chen, P.; Zhu, P.; Zheng, P.; Wang, T.; Wang, L.; Xu, C.; Zhou, J.; Zhang, H. Development of Small-Molecule BRD4 Degraders Based on Pyrrolopyridone Derivative. Bioorg. Chem. 2020, 99, 103817. https://doi.org/10.1016/j.bioorg.2020.103817.
    | |
  25. Sheppard, G. S.; Wang, L.; Fidanze, S. D.; Hasvold, L. A.; Liu, D.; Pratt, J. K.; Park, C. H.; Longenecker, K.; Qiu, W.; Torrent, M.; Kovar, P. J.; Bui, M.; Faivre, E.; Huang, X.; Lin, X.; Wilcox, D.; Zhang, L.; Shen, Y.; Albert, D. H.; Magoc, T. J.; Rajaraman, G.; Kati, W. M.; McDaniel, K. F. Discovery of N-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain. J. Med. Chem. 2020, 63 (10), 5585-5623. https://doi.org/10.1021/acs.jmedchem.0c00628.
    | |
  26. Tzvetkov, N. T.; Müller, C. E. Facile Synthesis of 5-Amino- and 7-Amino-6-Azaoxindole Derivatives. Tetrahedron Lett. 2012, 53 (42), 5597–5601. https://doi.org/10.1016/j.tetlet.2012.07.140.
    |
  27. Tzvetkov, N. T.; Müller, C. E. A Simple Approach to Multifunctionalized N1-Alkylated 7-Amino-6-azaoxindole Derivatives Using Their in Situ Stabilized Tautomer Form. Tetrahedron 2016, 72 (41), 6455–6466. https://doi.org/10.1016/j.tet.2016.08.055.
    |
  28. Veselovská, L.; Kudlová, N.; Gurská, S.; Lišková, B.; Medvedíková, M.; Hodek, O.; Tloušťová, E.; Milisavljevic, N.; Tichý, M.; Perlíková, P.; Mertlíková-Kaiserová, H.; Trylčová, J.; Pohl, R.; Klepetářová, B.; Džubák, P.; Hajdúch, M.; Hocek, M. Synthesis and Cytotoxic and Antiviral Activity Profiling of All-Four Isomeric Series of Pyrido-Fused 7-Deazapurine Ribonucleosides. Chem. – Eur. J. 2020, 26 (57), 13002–13015. https://doi.org/10.1002/chem.202001124.
    | |
  29. Reader, J. C.; Matthews, T. P.; Klair, S.; Cheung, K.-M.; Scanlon, J.; Proisy, N.; Addison, G.; Ellard, J.; Piton, N.; Taylor, S.; Cherry, M.; Fisher, M.; Boxall, K.; Burns, S.; Walton, M. I.; Westwood, I. M.; Hayes, A.; Eve, P.; Valenti, M.; de Haven Brandon, A.; Box, G.; van Montfort, R. L. M.; Williams, D. H.; Aherne, G. W.; Raynaud, F. I.; Eccles, S. A.; Garrett, M. D.; Collins, I. Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing. J. Med. Chem. 2011, 54 (24), 8328–8342. https://doi.org/10.1021/jm2007326.
    | |
  30. Söderberg, B. C. G.; Banini, S. R.; Turner, M. R.; Minter, A. R.; Arrington, A. K. Palladium-Catalyzed Synthesis of 3-Indolecarboxylic Acid Derivatives. Synthesis 2008, 6, 903–912. https://doi.org/10.1055/s-2008-1032208.
    |
  31. Walewska-Królikiewicz, M.; Wilk, B.; Kwast, A.; Wróbel, Z. Two-step, regioselective, multigram-scale synthesis of 2-(trifluoromethyl)indoles from 2-nitrotoluenes. Tetrahedron Lett. 2021, 86, 153515. https://doi.org/10.1016/j.tetlet.2021.153515.
    |
  32. Ivonin, S. P.; Yurchenko, A. A.; Voloshchuk, V. V.; Yurchenko, S. A.; Rusanov, E. B.; Pirozhenko, V. V.; Volochnyuk, D. M.; Kostyuk, A. N. A convenient approach to 3-trifluoromethyl-6-azaindoles. J. Fluorine Chem. 2020, 233, 109509. https://doi.org/10.1016/j.jfluchem.2020.109509.
    |
  33. Ivonin, S.; Voloshchuk, V.; Stepanova, D.; Ryabukhin, S.; Volochnyuk, D. Synthesis of 3-Formyl-6-Azaindoles via Vilsmeier-Haack Formylation of 3-Amino-4-Methyl Pyridines. ChemRxiv 2024. https://doi.org/10.26434/chemrxiv-2024-4ps8d.
  34. Ivonin, S. P.; Voloshchuk, V. V.; Rusanov, E. B.; Suikov, S.; Ryabukhin, S. V.; Volochnyuk, D. M. Synthesis of 6-azaindoles via formal electrophilic [4+1]-cyclization of 3-amino-4-methyl pyridines: new frontiers of diversity. Organic Chemistry Frontiers 2024, 11 (7), 2088-2094. https://doi.org/10.1039/D3QO01937C.
    |
  35. Luo, D.-Y.; Hu, X.-M.; Huang, R.; Cui, S.-S.; Yan, S.-J. Base-Promoted Relay Reaction of Heterocyclic Ketene Aminals with o-Difluorobenzene Derivatives for the Highly Site-Selective Synthesis of Functionalized Indoles. Tetrahedron 2021, 92, 132275. https://doi.org/10.1016/j.tet.2021.132275.
    |
  36. Beveridge, R. E.; Gerstenberger, B. S. A Direct Copper-Catalyzed Route to Pyrrolo-Fused Heterocycles from Boronic Acids. Tetrahedron Lett. 2012, 53 (5), 564–569. https://doi.org/10.1016/j.tetlet.2011.11.091.
    |
  37. Sathiyalingam, S.; Roesner, S. Synthesis of α- and β-Carbolines by a Metalation/Negishi Cross-Coupling/SNAr Reaction Sequence. Adv. Synth. Catal. 2022, 364 (10), 1769–1774. https://doi.org/10.1002/adsc.202200127.
    |
  38. Van Phuc, B.; Do, H. N.; Quan, N. M.; Tuan, N. N.; An, N. Q.; Van Tuyen, N.; Anh, H. L. T.; Hung, T. Q.; Dang, T. T.; Langer, P. Copper-Catalyzed Synthesis of β- and δ-Carbolines by Double N-Arylation of Primary Amines. Synlett 2021, 32 (10), 1004-1008. https://doi.org/10.1055/s-0040-1720461.
    |
  39. Hung, T. Q.; Hieu, D. T.; Tinh, D. V.; Do, H. N.; Nguyen Tien, T. A.; Do, D. V.; Son, L. T.; Tran, N. H.; Tuyen, N. V.; Tan, V. M.; Ehlers, P.; Dang, T. T.; Langer, P. Efficient Access to β- and γ-Carbolines from a Common Starting Material by Sequential Site-Selective Pd-Catalyzed C–C, C–N Coupling Reactions. Tetrahedron 2019, 75 (40), 130569. https://doi.org/10.1016/j.tet.2019.130569.
    |
  40. Ye, S.; Guo, R.; Wang, Y.; Duan, Y.; Wang, L. Exploiting Novel Electron-Deficient Moiety 2,5-Diazarcarbazole to Functionally Construct DPA-Containing Electron Transporting Materials for Highly Efficient Sky-Blue Fluorescent OLEDs. Dyes Pigm. 2021, 185, 108935. https://doi.org/10.1016/j.dyepig.2020.108935.
    |
  41. Li, Z.; Wang, X.; Eksterowicz, J.; Gribble, M. W., Jr.; Alba, G. Q.; Ayres, M.; Carlson, T. J.; Chen, A.; Chen, X.; Cho, R.; Connors, R. V.; DeGraffenreid, M.; Deignan, J. T.; Duquette, J.; Fan, P.; Fisher, B.; Fu, J.; Huard, J. N.; Kaizerman, J.; Keegan, K. S.; Li, C.; Li, K.; Li, Y.; Liang, L.; Liu, W.; Lively, S. E.; Lo, M.-C.; Ma, J.; McMinn, D. L.; Mihalic, J. T.; Modi, K.; Ngo, R.; Pattabiraman, K.; Piper, D. E.; Queva, C.; Ragains, M. L.; Suchomel, J.; Thibault, S.; Walker, N.; Wang, X.; Wang, Z.; Wanska, M.; Wehn, P. M.; Weidner, M. F.; Zhang, A. J.; Zhao, X.; Kamb, A.; Wickramasinghe, D.; Dai, K.; McGee, L. R.; Medina, J. C. Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3. J. Med. Chem. 2014, 57 (8), 3430-3449. https://doi.org/10.1021/jm500118j.
    | |
  42. Şendil, K.; Keskin, S.; Balci, M. Concise Design and Synthesis of Pyridine-Fused Heterocycles via 6π-Azaelectrocyclization Process of Iminoalkyne Derivatives. Tetrahedron 2019, 75 (46), 130660. https://doi.org/10.1016/j.tet.2019.130660.
    |
  43. Uredi, D.; Motati, D. R.; Watkins, E. B. A Unified Strategy for the Synthesis of β-Carbolines, γ-Carbolines, and Other Fused Azaheteroaromatics under Mild, Metal-Free Conditions. Org. Lett. 2018, 20 (20), 6336–6339. https://doi.org/10.1021/acs.orglett.8b02441.
    | |
  44. Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. Iodine-Mediated Electrophilic Cyclization of 2-Alkynyl-1-methylene Azide Aromatics Leading to Highly Substituted Isoquinolines and Its Application to the Synthesis of Norchelerythrine. J. Am. Chem. Soc. 2008, 130 (46), 15720–15725. https://doi.org/10.1021/ja805326f.
    | |
  45. Johnson, T. W.; Tanis, S. P.; Butler, S. L.; Dalvie, D.; DeLisle, D. M.; Dress, K. R.; Flahive, E. J.; Hu, Q.; Kuehler, J. E.; Kuki, A.; Liu, W.; McClellan, G. A.; Peng, Q.; Plewe, M. B.; Richardson, P. F.; Smith, G. L.; Solowiej, J.; Tran, K. T.; Wang, H.; Yu, X.; Zhang, J.; Zhu, H. Design and Synthesis of Novel N-Hydroxy-Dihydronaphthyridinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors. J. Med. Chem. 2011, 54 (9), 3393-3417. https://doi.org/10.1021/jm200208d.
    | |
  46. Phatake, R. S.; Patel, P.; Ramana, C. V. Ir(III)-Catalyzed Synthesis of Isoquinoline N‑Oxides from Aryloxime and α‑Diazocarbonyl Compounds. Org. Lett. 2016, 18 (2), 292–295. https://doi.org/10.1021/acs.orglett.5b03462.
    | |
  47. Abdelwaly, A.; Salama, I.; Gomaa, M. S.; Helal, M. A. Discovery of Tetrahydro-β-Carboline Derivatives as a New Class of Phosphodiesterase 4 Inhibitors. Med. Chem. Res. 2017, 26 (12), 3173–3187. https://doi.org/10.1007/s00044-017-2011-x.
    |
  48. Buaban, K.; Phutdhawong, W.; Taechowisan, T.; Phutdhawong, W. S. Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of Plant Pathogenic Fungi. Molecules 2021, 26 (1), 207. https://doi.org/10.3390/molecules26010207.
    | |
  49. Bertamino, A.; Ostacolo, C.; Medina, A.; Di Sarno, V.; Lauro, G.; Ciaglia, T.; Vestuto, V.; Pepe, G.; Basilicata, M. G.; Musella, S.; Smaldone, G.; Cristiano, C.; Gonzalez-Rodriguez, S.; Fernandez-Carvajal, A.; Bifulco, G.; Campiglia, P.; Gomez-Monterrey, I.; Russo, R. Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities. J. Med. Chem. 2020, 63 (17), 9672-9694. https://doi.org/10.1021/acs.jmedchem.0c00816.
    | |
  50. Xin, B.; Tang, W.; Wang, Y.; Lin, G.; Liu, H.; Jiao, Y.; Zhu, Y.; Yuan, H.; Chen, Y.; Lu, T. Design, Synthesis, and Biological Evaluation of β-Carboline Derivatives as Novel Inhibitors Targeting B-Raf Kinase. Bioorg. Med. Chem. Lett. 2012, 22 (14), 4783–4786. https://doi.org/10.1016/j.bmcl.2012.05.053.
    | |
  51. Sheng, T.; Kong, M.; Wang, Y.; Wu, H.; Gu, Q.; Chuang, A. S.; Li, S.; Gao, X. Discovery and Preliminary Mechanism of 1-Carbamoyl β-Carbolines as New Antifungal Candidates. Eur. J. Med. Chem. 2021, 222, 113563. https://doi.org/10.1016/j.ejmech.2021.113563.
    | |
  52. Szabó, T.; Hazai, V.; Volk, B.; Simig, G.; Milen, M. First Total Synthesis of the β-Carboline Alkaloids Trigonostemine A, Trigonostemine B and a New Synthesis of Pityriacitrin and Hyrtiosulawesine. Tetrahedron Lett. 2019, 60 (22), 1471–1475. https://doi.org/10.1016/j.tetlet.2019.04.044.
    |
  53. Zhao, Z.; Sun, Y.; Wang, L.; Chen, X.; Sun, Y.; Lin, L.; Tang, Y.; Li, F.; Chen, D. Organic Base-Promoted Efficient Dehydrogenative/Decarboxylative Aromatization of Tetrahydro-β-Carbolines into β-Carbolines Under Air. Tetrahedron Lett. 2019, 60 (11), 800–804. https://doi.org/10.1016/j.tetlet.2019.02.020.
    |
  54. Ikeda, R.; Iwaki, T.; Iida, T.; Okabayashi, T.; Nishi, E.; Kurosawa, M.; Sakai, N.; Konakahara, T. 3-Benzylamino-β-carboline Derivatives Induce Apoptosis through G2/M Arrest in Human Carcinoma Cells HeLa S-3. Eur. J. Med. Chem. 2011, 46 (2), 636-646. https://doi.org/10.1016/j.ejmech.2010.11.044.
    | |
  55. Ikeda, R.; Kimura, T.; Tsutsumi, T.; Tamura, S.; Sakai, N.; Konakahara, T. Structure–Activity Relationship in the Antitumor Activity of 6-, 8- or 6,8-Substituted 3-Benzylamino-β-Carboline Derivatives. Bioorg. Med. Chem. Lett. 2012, 22 (14), 3506–3515. https://doi.org/10.1016/j.bmcl.2012.03.077.
    | |
  56. Xu, W.; Zhao, M.; Wang, Y.; Zhu, H.; Wang, Y.; Zhao, S.; Wu, J.; Peng, S. Design, Synthesis, In Vivo Evaluations of Benzyl Nω-nitro-Nα-(9H-pyrido[3,4-b]indole-3-carbonyl)-L-argininate as Apoptosis Inducer Capable of Decreasing Serum Concentration of P-selectin. Med. Chem. Commun. 2016, 7 (9), 1730–1737. https://doi.org/10.1039/C6MD00215C.
    |
  57. Ling, Y.; Gao, W.-J.; Ling, C.; Liu, J.; Meng, C.; Qian, J.; Liu, S.; Gan, H.; Wu, H.; Tao, J.; Dai, H.; Zhang, Y. β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma. Eur. J. Med. Chem. 2019, 168, 515-526. https://doi.org/10.1016/j.ejmech.2019.02.054.
    | |
  58. Gu, H.; Li, N.; Dai, J.; Xi, Y.; Wang, S.; Wang, J. Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target. Int. J. Mol. Sci. 2018, 19 (10), 3179. https://doi.org/10.3390/ijms19103179.
    | |
  59. Lan, J.-S.; Xie, S.-S.; Li, S.-Y.; Pan, L.-F.; Wang, X.-B.; Kong, L.-Y. Design, Synthesis and Evaluation of Novel Tacrine-(β-carboline) Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease. Bioorg. Med. Chem. 2014, 22 (21), 6089-6104. https://doi.org/10.1016/j.bmc.2014.08.035.
    | |
  60. Misra, S.; Ghatak, S.; Patil, N.; Dandawate, P.; Ambike, V.; Adsule, S.; Unni, D.; Venkateswara Swamy, K.; Padhye, S. Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan–CD44v6 pathway and inducing cytotoxicity in colon cancer cells. Bioorg. Med. Chem. 2013, 21 (9), 2551-2559. https://doi.org/10.1016/j.bmc.2013.02.033.
    | |
  61. Lu, X.; Liu, Y.-C.; Orvig, C.; Liang, H.; Chen, Z.-F. Discovery of β-carboline copper(II) complexes as Mcl-1 inhibitor and in vitro and in vivo activity in cancer models. Eur. J. Med. Chem. 2019, 181, 111567. https://doi.org/10.1016/j.ejmech.2019.111567.
    | |
  62. Skrott, Z.; Mistrik, M.; Andersen, K. K.; Friis, S.; Majera, D.; Gursky, J.; Ozdian, T.; Bartkova, J.; Turi, Z.; Moudry, P.; Kraus, M.; Michalova, M.; Vaclavkova, J.; Dzubak, P.; Vrobel, I.; Pouckova, P.; Sedlacek, J.; Miklovicova, A.; Kutt, A.; Li, J.; Mattova, J.; Driessen, C.; Dou, Q. P.; Olsen, J.; Hajduch, M.; Cvek, B.; Deshaies, R. J.; Bartek, J. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 2017, 552 (7684), 194-199. https://doi.org/10.1038/nature25016.
    | |
  63. Tang, J.-G.; Liu, H.; Zhou, Z.-Y.; Liu, J.-K. Facile and Efficient One-Pot Synthesis of β-Carbolines. Synth. Commun. 2010, 40 (10), 1411–1417. https://doi.org/10.1080/00397910903097245.
    |
  64. Wang, Z.-X.; Xiang, J.-C.; Cheng, Y.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-X. Direct Biomimetic Synthesis of β-Carboline Alkaloids from Two Amino Acids. J. Org. Chem. 2018, 83 (19), 12247-12254. https://doi.org/10.1021/acs.joc.8b01668.
    | |
  65. Wang, Z.; Yu, Z.; Yao, Y.; Zhang, Y.; Xiao, X.; Wang, B. A practical synthesis of β-carbolines by tetra-n-butylammonium bromide (TBAB)-mediated cycloaromatization reaction of aldehydes with tryptophan derivatives. Chin. Chem. Lett. 2019, 30 (8), 1541-1544. https://doi.org/10.1016/j.cclet.2019.07.001.
    |
  66. Pichette Drapeau, M.; Tlili, A. Modern synthesis of carbamoyl fluorides. Tetrahedron Lett. 2020, 61 (47), 152539. https://doi.org/10.1016/j.tetlet.2020.152539.
    |
  67. Schwalm, C. S.; Correia, C. R. D. Divergent total synthesis of the natural antimalarial marinoquinolines A, B, C, E and unnatural analogues. Tetrahedron Lett. 2012, 53 (36), 4836-4840. https://doi.org/10.1016/j.tetlet.2012.06.115.
    |
  68. Aguiar, A. C. C.; Panciera, M.; Simão dos Santos, E. F.; Singh, M. K.; Garcia, M. L.; de Souza, G. E.; Nakabashi, M.; Costa, J. L.; Garcia, C. R. S.; Oliva, G.; Correia, C. R. D.; Guido, R. V. C. Discovery of Marinoquinolines as Potent and Fast-Acting Plasmodium falciparum Inhibitors with in vivo Activity. J. Med. Chem. 2018, 61 (13), 5547–5568. https://doi.org/10.1021/acs.jmedchem.8b00143.
    | |
  69. Akula, M.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D.; Bhattacharya, A. New Class of Antitubercular Compounds: Synthesis and Anti-Tubercular Activity of 4-Substituted Pyrrolo[2,3-c]quinolines. Monatsh. Chem. 2014, 145 (5), 811–819. https://doi.org/10.1007/s00706-013-1141-1.
    |
  70. Nishiyama, T.; Hamada, E.; Ishii, D.; Kihara, Y.; Choshi, N.; Nakanishi, N.; Murakami, M.; Taninaka, K.; Hatae, N.; Choshi, T. Total Synthesis of Pyrrolo[2,3-c]quinoline Alkaloid: Trigonoine B. Beilstein J. Org. Chem. 2021, 17, 730–736. https://doi.org/10.3762/bjoc.17.62.
    | |
  71. Mahajan, J. P.; Suryawanshi, Y. R.; Mhaske, S. B. Pd-Catalyzed Imine Cyclization: Synthesis of Antimalarial Natural Products Aplidiopsamine A, Marinoquinoline A, and Their Potential Hybrid NCLite-M1. Org. Lett. 2012, 14 (22), 5804–5807. https://doi.org/10.1021/ol302676v.
    | |
  72. Osano, M.; Jhaveri, D. P.; Wipf, P. Formation of 6‑Azaindoles by Intramolecular Diels−Alder Reaction of Oxazoles and Total Synthesis of Marinoquinoline A. Org. Lett. 2020, 22 (6), 2215–2219. https://doi.org/10.1021/acs.orglett.0c00417.
    | |
  73. Mulcahy, S. P.; Varelas, J. G. Three-step synthesis of an annulated β-carboline via palladium catalysis. Tetrahedron Lett. 2013, 54 (48), 6599–6601. https://doi.org/10.1016/j.tetlet.2013.09.108.
    | |
  74. Varelas, J. G.; Khanal, S.; O’Donnell, M. A.; Mulcahy, S. P. Concise Synthesis of Annulated Pyrido[3,4‑b]indoles via Rh(I)-Catalyzed Cyclization. Org. Lett. 2015, 17 (21), 5512–5514. https://doi.org/10.1021/acs.orglett.5b02807.
    | |
  75. Saliba, B. M.; Khanal, S.; O’Donnell, M. A.; Queenan, K. E.; Song, J.; Gentile, M. R.; Mulcahy, S. P. Parallel Strategies for the Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)- and Pd(0)-catalyzed Cyclotrimerization. Tetrahedron Lett. 2018, 59 (49), 4311–4314. https://doi.org/10.1016/j.tetlet.2018.10.050.
    | |
  76. Wang, T.; Ueda, Y.; Zhang, Z.; Yin, Z.; Matiskella, J.; Pearce, B. C.; Yang, Z.; Zheng, M.; Parker, D. D.; Yamanaka, G. A.; Gong, Y.-F.; Ho, H.-T.; Colonno, R. J.; Langley, D. R.; Lin, P.-F.; Meanwell, N. A.; Kadow, J. F. Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir. J. Med. Chem. 2018, 61 (13), 6308–6327. https://doi.org/10.1021/acs.jmedchem.8b00759.
    | |
  77. Boutin, M.; Vézina, D.; Ding, S.; Prévost, J.; Laumaea, A.; Marchitto, L.; Anand, S. P.; Medjahed, H.; Gendron-Lepage, G.; Bourassa, C.; Goyette, G.; Clark, A.; Richard, J.; Finzi, A. Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies. mBio 2022, 13 (3), e00577-22. https://doi.org/10.1128/mbio.00577-22.
    | |
  78. Kamal, A.; Tangella, Y.; Kesari, M. L.; Manda, S.; Srinivasulu, V.; Jadala, C.; Alarifi, A. PhI(OAc)2-Mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-β-carbolines: synthesis of norharmane, harmane, eudistomin U, and eudistomin I. Org. Biomol. Chem. 2015, 13 (32), 8652–8662. https://doi.org/10.1039/C5OB00871A.
    | |
  79. Li, S.-F.; Di, Y.-T.; He, H.-P.; Zhang, Y.; Wang, Y.-H.; Yin, J.-L.; Tan, C.-J.; Lin, S.-L.; Hao, X.-J. Trigonoines A and B, Two Novel Alkaloids from the Leaves of Trigonostemon lii. Tetrahedron Lett. 2011, 52 (22), 3186–3188. https://doi.org/10.1016/j.tetlet.2011.03.015.
    |
  80. Carroll, A. R.; Duffy, S.; Avery, V. M. Aplidiopsamine A, an Antiplasmodial Alkaloid from the Temperate Australian Ascidian, Aplidiopsis confluata. J. Org. Chem. 2010, 75 (23), 8291–8294. https://doi.org/10.1021/jo101695v.
    | |
  81. Sangnoi, Y.; Sakulkeo, O.; Yuenyongsawad, S.; Kanjana-opas, A.; Ingkaninan, K.; Plubrukarn, A.; Suwanborirux, K. Acetylcholinesterase-Inhibiting Activity of Pyrrole Derivatives from a Novel Marine Gliding Bacterium, Rapidithrix thailandica. Marine Drugs 2008, 6 (4), 578-586. https://doi.org/10.3390/md6040578.
    | |
  82. England, D. B.; Padwa, A. Gold-Catalyzed Cycloisomerization of N-Propargylindole-2-carboxamides: Application toward the Synthesis of Lavendamycin Analogues. Org. Lett. 2008, 10 (16), 3631–3634. https://doi.org/10.1021/ol801385h.
    | |
  83. Stephens, D. N.; Schneider, H. H.; Kehr, W.; Andrews, J. S.; Rettig, K. J.; Turski, L.; Schmiechen, R.; Turner, J. D.; Jensen, L. H.; Petersen, E. N. Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors. J. Pharmacol. Exp. Ther. 1990, 253 (1), 334-343.
    |
  84. Zhao, Y.; Ye, F.; Xu, J.; Liao, Q.; Chen, L.; Zhang, W.; Sun, H.; Liu, W.; Feng, F.; Qu, W. Design, Synthesis, and Evaluation of Novel Bivalent β-Carboline Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease. Bioorg. Med. Chem. 2018, 26 (13), 3812–3824. https://doi.org/10.1016/j.bmc.2018.06.018.
    | |

Downloads

Published

2024-06-19

How to Cite

(1)
Voloshchuk, V. V.; Ivonin, S. P. Recent Advances in the Synthesis and Biological Activity of Pyrrolo[2,3-c]pyridines. J. Org. Pharm. Chem. 2024, 22, 33-56.

Issue

Vol. 22 No. 1 (2024)

Section

Review Articles

License

Copyright (c) 2024 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).