Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies
Isocyanide-based multicomponent reactions turn out to be interesting synthetic strategies, with highly valued advantages such as atomic economy, selectivity, among others. Furthermore, Isocyanide-based multicomponent reactions have been shown to generate a wide range of products with significant bio...
- Autores:
-
Camargo-Ayala, Lorena
Polo-Cuadrado, Efraín
Osorio, Edison
Soto-Delgado, Jorge
Duarte, Yorley
Prent-Peñaloza, Luis
Gutiérrez, Margarita
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2022
- Institución:
- Universidad de Ibagué
- Repositorio:
- Repositorio Universidad de Ibagué
- Idioma:
- eng
- OAI Identifier:
- oai:repositorio.unibague.edu.co:20.500.12313/5501
- Acceso en línea:
- https://hdl.handle.net/20.500.12313/5501
- Palabra clave:
- Alzheimer
Alzheimer - Inhibidores de butirilcolinesterasa
Alzheimer's disease
Butyrylcholinesterase inhibitors
IMCR
- Rights
- openAccess
- License
- © 2022 Elsevier B.V. All rights reserved.
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Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| title |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| spellingShingle |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies Alzheimer Alzheimer - Inhibidores de butirilcolinesterasa Alzheimer's disease Butyrylcholinesterase inhibitors IMCR |
| title_short |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| title_full |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| title_fullStr |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| title_full_unstemmed |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| title_sort |
Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies |
| dc.creator.fl_str_mv |
Camargo-Ayala, Lorena Polo-Cuadrado, Efraín Osorio, Edison Soto-Delgado, Jorge Duarte, Yorley Prent-Peñaloza, Luis Gutiérrez, Margarita |
| dc.contributor.author.none.fl_str_mv |
Camargo-Ayala, Lorena Polo-Cuadrado, Efraín Osorio, Edison Soto-Delgado, Jorge Duarte, Yorley Prent-Peñaloza, Luis Gutiérrez, Margarita |
| dc.subject.armarc.none.fl_str_mv |
Alzheimer Alzheimer - Inhibidores de butirilcolinesterasa |
| topic |
Alzheimer Alzheimer - Inhibidores de butirilcolinesterasa Alzheimer's disease Butyrylcholinesterase inhibitors IMCR |
| dc.subject.proposal.eng.fl_str_mv |
Alzheimer's disease Butyrylcholinesterase inhibitors IMCR |
| description |
Isocyanide-based multicomponent reactions turn out to be interesting synthetic strategies, with highly valued advantages such as atomic economy, selectivity, among others. Furthermore, Isocyanide-based multicomponent reactions have been shown to generate a wide range of products with significant biological activity. Recently, it has been described that the compounds of the Isocyanide-based multicomponent reactions product could be inhibitors of cholinesterase enzymes, acetylcholinesterase, and butyrylcholinesterase. cholinesterase enzymes have aroused great interest as pharmacological targets in the treatment of Alzheimer’s disease, which is a disease that affects millions of people in the world, and its effects become disabling for those who suffer from it since it mainly has consequences on memory and cognitive ability. In this work, using Isocyanide-based multicomponent reactions, we report a series of five new compounds, their characterization, and their potential inhibitory biological activity on acetylcholinesterase and butyrylcholinesterase by spectrophotometric analysis. Our studies revealed that the compounds have moderate inhibitory activities against acetylcholinesterase and butyrylcholinesterase. Interestingly, compounds 7a and 7e showed a higher affinity for butyrylcholinesterase. Particularly compound 7a proved to be the compound with the best activity of this series with an IC50 of 25.91 μM for butyrylcholinesterase, more than 62.22 times selective for butyrylcholinesterase than for acetylcholinesterase. The study of molecular docking and molecular dynamics revealed that the hydrophobic character of these compounds favors the interaction with BChE. The favored interactions for compounds 7a and 7e are with the hydrophobic residues Trp82, Trp231, Val288, Phe329, Thr120. In addition, the molecular electrostatic potential and pharmacokinetic predictions also showed that compounds 7a and 7e have free energy values close to galantamine in the complex with butyrylcholinesterase, among others. These analyzes will allow us in the future to establish some structural modifications that would enable, on this basis, to obtain compounds with better activity against cholinesterase enzymes. |
| publishDate |
2022 |
| dc.date.issued.none.fl_str_mv |
2022-09-15 |
| dc.date.accessioned.none.fl_str_mv |
2025-08-20T21:11:56Z |
| dc.date.available.none.fl_str_mv |
2025-08-20T21:11:56Z |
| dc.type.none.fl_str_mv |
Artículo de revista |
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http://purl.org/coar/resource_type/c_2df8fbb1 |
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http://purl.org/coar/version/c_970fb48d4fbd8a85 |
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Text |
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info:eu-repo/semantics/article |
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Camargo-Ayala, L., Polo-Cuadrado, E., Osorio, E., Soto-Delgado, J., Duarte, Prent-Peñaloza, L y Gutiérrez, M. (2022). Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies. Journal of Molecular Structure, 1264, 133307. DOI: 10.1016/j.molstruc.2022.133307 |
| dc.identifier.doi.none.fl_str_mv |
10.1016/j.molstruc.2022.133307 |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/20.500.12313/5501 |
| identifier_str_mv |
Camargo-Ayala, L., Polo-Cuadrado, E., Osorio, E., Soto-Delgado, J., Duarte, Prent-Peñaloza, L y Gutiérrez, M. (2022). Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies. Journal of Molecular Structure, 1264, 133307. DOI: 10.1016/j.molstruc.2022.133307 10.1016/j.molstruc.2022.133307 |
| url |
https://hdl.handle.net/20.500.12313/5501 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
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133307 |
| dc.relation.citationvolume.none.fl_str_mv |
1264 |
| dc.relation.ispartofjournal.none.fl_str_mv |
Journal of Molecular Structure |
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I. Ugi, A. Dömling, W. Hörl, Multicomponent reactions in organic chemistry, Endeavour 18 (1994) 115–122, doi:10.1016/S0160-9327(05)80086- 9. E. Ruijter, R. Orru, Multicomponent reactions in drug discovery and medicinal chemistry, Drug Discov. Today Technol. 29 (2018) 1–2, doi:10.1016/j.ddtec.2018. 11.002. A. Shaabani, R. Mohammadian, R. Afshari, S.E. Hooshmand, M.T. Nazeri, S. Javanbakht, The status of isocyanide-based multi-component reactions in Iran (2010–2018), Mol. Divers. 252 (25) (2020) 1145–1210 2020, doi:10.1007/ S11030-020-10049-7. I. Ugi, R. Meyr, I Isonitrile, Darstellung von isonitrilen aus monosubstituierten formamiden durch wasserabspaltung, Chem. Ber. 93 (1960) 239–248, doi:10. 1002/cber.19600930136. I. Ugi, R. Meyr, Neue Darstellungsmethode für Isonitrile, Angew. Chem. 70 (1958) 702–703, doi:10.1002/ange.19580702213. B. Banerjee, Recent developments on ultrasound-assisted one-pot multicomponent synthesis of biologically relevant heterocycles, Ultrason. Sonochem. 35 (2017) 15–35, doi:10.1016/j.ultsonch.2016.10.010. A. Dömling∗, Recent developments in isocyanide based multicomponent reactions in applied chemistry†, Chem. Rev. 106 (2005) 17–89, doi:10.1021/ CR0505728. I. Pachón-Angona, H. Martin, S. Chhor, M.J. Oset-Gasque, B. Refouvelet, J. Marco-Contelles, L. Ismaili, Synthesis of new ferulic/lipoic/comenic acidmelatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction, Future Med. Chem. 11 (2019) 3097–3108, doi:10.4155/fmc-2019-0191. M. Ingold, L. Colella, P. Hernández, C. Batthyány, D. Tejedor, A. Puerta, F. GarcíaTellado, J.M. Padrón, W. Porcal, G.V. López, A focused library of no-donor compounds with potent antiproliferative activity based on green multicomponent reactions, ChemMedChem 14 (2019) 1669–1683, doi:10.1002/cmdc. 201900385 E. Avilés, J. Prudhomme, K.G. Le Roch, S.G. Franzblau, K. Chandrasena, A.M.S. Mayer, A.D. Rodríguez, Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold, Bioorganic Med. Chem. Lett. 25 (2015) 5339–5343, doi:10.1016/j.bmcl.2015.09.033. L. Prent-Peñaloza, A.F. De La Torre, J.L. Velázquez-Libera, M. Gutiérrez, J. Caballero, Synthesis of DiN-substituted glycyl-phenylalanine derivatives by using Ugi four component reaction and their potential as acetylcholinesterase inhibitors, Molecules (2019) 24, doi:10.3390/molecules24010189. N. Cankarová, ˇ V. Krchnák, ˇ Isocyanide multicomponent reactions on solid phase: state of the art and future application, Int. J. Mol. Sci. 21 (2020) 1–48, doi:10.3390/IJMS21239160. R. Munir, M. Zia-ur-Rehman, S. Murtaza, S. Zaib, N. Javid, S.J. Awan, K. Iftikhar, M.M. Athar, I. Khan, Microwave-assisted synthesis of (piperidin1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as potent inhibitors of cholinesterases: a biochemical and in silico approach, Molecules 26 (2021) 656, doi:10.3390/molecules26030656. Z. Breijyeh, R. Karaman, Comprehensive review on alzheimer’s disease: causes and treatment, Molecules (2020) 25, doi:10.3390/MOLECULES25245789. D. Munoz-Torrero, Acetylcholinesterase inhibitors as disease-modifying therapies for alzheimers disease, Curr. Med. Chem. 15 (2008) 2433–2455, doi:10. 2174/092986708785909067. R.T. Bartus, R.L. Dean, B. Beer, A.S. Lippa, The cholinergic hypothesis of geriatric memory dysfunction, Science (80-.) 217 (1982) 408–417, doi:10.1126/science. 7046051. T. Zhao, K.M. Ding, L. Zhang, X.M. Cheng, C.H. Wang, Z.T. Wang, Acetylcholinesterase and butyrylcholinesterase inhibitory activities of β -carboline and quinoline alkaloids derivatives from the plants of genus peganum, J. Chem. (2013) 2013, doi:10.1155/2013/717232. N.H. Greig, T. Utsuki, Q. Yu, X. Zhu, H.W. Holloway, T. Perry, B. Lee, D.K. Ingram, D.K. Lahiri, A New Therapeutic Target in Alzheimer’s Disease Treatment: attention to Butyrylcholinesterase, Curr. Med. Res. Opin 17 (2001) 159–165, doi:10.1185/0300799039117057. Q. Li, H. Yang, Y. Chen, H. Sun, Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer’s disease, Eur. J. Med. Chem. 132 (2017) 294–309, doi:10.1016/j.ejmech.2017.03.062. N.H. Greig, T. Utsuki, D.K. Ingram, Y. Wang, G. Pepeu, C. Scali, Q.S. Yu, J. Mamczarz, H.W. Holloway, T. Giordano, D. Chen, K. Furukawa, K. Sambamurti, A. Brossi, D.K. Lahiri, Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 17213–17218, doi:10.1073/pnas. 0508575102. P. Brandão, Ó. López, L. Leitzbach, H. Stark, J.G. Fernández-Bolaños, A.J. Burke, M. Pineiro, Ugi reaction synthesis of oxindole–lactam hybrids as selective butyrylcholinesterase inhibitors, ACS Med. Chem. Lett. (2021), doi:10.1021/ ACSMEDCHEMLETT.1C00344. M. Pineiro, Ugi reacD. E. Shaw Research, New York, NY, Release 2021-2:, Desmond Molecular Dynamics SystemMaestro-Desmond Interoperability Tools 2021, Schrödinger, New York, NY, 2021. T. Tubiana, J.C. Carvaillo, Y. Boulard, S. Bressanelli, TTClust: a versatile molecular simulation trajectory clustering program with graphical summaries, J. Chem. Inf. Model. 58 (2018) 2178–2182, doi:10.1021/ACS.JCIM.8B00512/SUPPL_ FILE/CI8B00512_SI_001.PDF. H. Chermette, Chemical reactivity indexes in density functional theory, J. Comput. Chem. 20 (1999) 129–154, doi:10.1002/(SICI)1096-987X(19990115)20: 1 129::AID-JCC13 3.0.CO;2-A A. Daina, O. Michielin, V. Zoete, SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep. 7 (2017) 42717, doi:10.1038/srep42717. G.L. Ellman, K.D. Courtney, V. Andres, R.M. Featherstone, A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol. 7 (1961) 88–95, doi:10.1016/0006-2952(61)90145-9. H.M. Greenblatt, G. Kryger, T. Lewis, I. Silman, J.L. Sussman, Structure of acetylcholinesterase complexed with (−)-galanthamine at 2.3A˚ resolution, FEBS Lett 463 (1999) 321–326, doi:10.1016/S0014-5793(99)01637-3. F. Nachon, E. Carletti, C. Ronco, M. Trovaslet, Y. Nicolet, L. Jean, P.Y. Renard, Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase, Biochem. J. 453 (2013) 393–399, doi:10. 1042/BJ20130013. A.D. Becke, Density-functional thermochemistry. III. The role of exact exchange, J. Chem. Phys. 98 (1993) 5648–5652, doi:10.1063/1.464913. C. Lee, W. Yang, R.G. 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Stratmann, A. Yazyev, R. Austin, C. Cammi, J. Pomelli, P. Ochterski, K. Ayala, G. Morokuma, P. Voth, J. Salvador, V. Dannenberg, S. Zakrzewski, A. Dapprich, M. Daniels, O. Strain, D. Farkas, A. Malick, K. Rabuck, J. Raghavachari, J. Foresman, Q. Ortiz, A. Cui, S. Baboul, J. Clifford, B. Cioslowski, G. Stefanov, A. Liu, P. Liashenko, I. Piskorz, R. Komaromi, D. Martin, T. Fox, A. Keith, C. Laham, A. Peng, M. Nanayakkara, P. Challacombe, B. Gill, W. Johnson, M. Chen, C. Wong, J. Gonzalez, Pople, Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT, 2009. G.M. Morris, H. Ruth, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.J. Olson, Software news and updates AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility, J. Comput. Chem. 30 (2009) 2785–2791, doi:10.1002/jcc.21256. G.M. Morris, D.S. Goodsell, R.S. Halliday, R. Huey, W.E. Hart, R.K. Belew, A.J. Olson, Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function, J. Comput. Chem. 19 (1998) 1639–1662, doi:10.1002/(SICI)1096-987X(19981115)19:14 1639::AID-JCC10 3.0.CO;2-B W.L. DeLano, The PyMOL molecular graphics system, (2002). http://www. pymol.org S. Salentin, S. Schreiber, V.J. Haupt, M.F. Adasme, M. Schroeder, PLIP: fully automated protein–ligand interaction profiler, Nucleic Acids Res. 43 (2015) W443– W447, doi:10.1093/NAR/GKV315. M.P. Jacobson, D.L. Pincus, C.S. Rapp, T.J.F. Day, B. Honig, D.E. Shaw, R.A. Friesner, A hierarchical approach to all-atom protein loop prediction, Proteins Struct. Funct. Bioinforma. 55 (2004) 351–367, doi:10.1002/prot.10613. |
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Camargo-Ayala, Lorena41c900ab-b356-4c05-8594-1f10c2d6c414-1Polo-Cuadrado, Efraínf8016ac0-3f43-4599-89b2-3d8e129cb357-1Osorio, Edisone6d834e4-46ca-40f0-ab7c-630a35856901-1Soto-Delgado, Jorge70e6a31a-d113-49de-a9fd-df5b0278031c-1Duarte, Yorley6fcc279c-c6a8-44fc-81b7-5b806866caff-1Prent-Peñaloza, Luis75975bd9-cd4e-48b6-99cd-2cbb8f0b1dd9-1Gutiérrez, Margarita3d6c891b-b6e6-4157-b398-c6ef08538087-12025-08-20T21:11:56Z2025-08-20T21:11:56Z2022-09-15Isocyanide-based multicomponent reactions turn out to be interesting synthetic strategies, with highly valued advantages such as atomic economy, selectivity, among others. Furthermore, Isocyanide-based multicomponent reactions have been shown to generate a wide range of products with significant biological activity. Recently, it has been described that the compounds of the Isocyanide-based multicomponent reactions product could be inhibitors of cholinesterase enzymes, acetylcholinesterase, and butyrylcholinesterase. cholinesterase enzymes have aroused great interest as pharmacological targets in the treatment of Alzheimer’s disease, which is a disease that affects millions of people in the world, and its effects become disabling for those who suffer from it since it mainly has consequences on memory and cognitive ability. In this work, using Isocyanide-based multicomponent reactions, we report a series of five new compounds, their characterization, and their potential inhibitory biological activity on acetylcholinesterase and butyrylcholinesterase by spectrophotometric analysis. Our studies revealed that the compounds have moderate inhibitory activities against acetylcholinesterase and butyrylcholinesterase. Interestingly, compounds 7a and 7e showed a higher affinity for butyrylcholinesterase. Particularly compound 7a proved to be the compound with the best activity of this series with an IC50 of 25.91 μM for butyrylcholinesterase, more than 62.22 times selective for butyrylcholinesterase than for acetylcholinesterase. The study of molecular docking and molecular dynamics revealed that the hydrophobic character of these compounds favors the interaction with BChE. The favored interactions for compounds 7a and 7e are with the hydrophobic residues Trp82, Trp231, Val288, Phe329, Thr120. In addition, the molecular electrostatic potential and pharmacokinetic predictions also showed that compounds 7a and 7e have free energy values close to galantamine in the complex with butyrylcholinesterase, among others. These analyzes will allow us in the future to establish some structural modifications that would enable, on this basis, to obtain compounds with better activity against cholinesterase enzymes.application/pdfCamargo-Ayala, L., Polo-Cuadrado, E., Osorio, E., Soto-Delgado, J., Duarte, Prent-Peñaloza, L y Gutiérrez, M. (2022). Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies. Journal of Molecular Structure, 1264, 133307. DOI: 10.1016/j.molstruc.2022.13330710.1016/j.molstruc.2022.133307https://hdl.handle.net/20.500.12313/5501engElsevier B.V.Paises Bajos1333071264Journal of Molecular StructureI. Ugi, A. Dömling, W. Hörl, Multicomponent reactions in organic chemistry, Endeavour 18 (1994) 115–122, doi:10.1016/S0160-9327(05)80086- 9.E. Ruijter, R. Orru, Multicomponent reactions in drug discovery and medicinal chemistry, Drug Discov. Today Technol. 29 (2018) 1–2, doi:10.1016/j.ddtec.2018. 11.002.A. Shaabani, R. Mohammadian, R. Afshari, S.E. Hooshmand, M.T. Nazeri, S. Javanbakht, The status of isocyanide-based multi-component reactions in Iran (2010–2018), Mol. Divers. 252 (25) (2020) 1145–1210 2020, doi:10.1007/ S11030-020-10049-7.I. Ugi, R. Meyr, I Isonitrile, Darstellung von isonitrilen aus monosubstituierten formamiden durch wasserabspaltung, Chem. Ber. 93 (1960) 239–248, doi:10. 1002/cber.19600930136.I. Ugi, R. Meyr, Neue Darstellungsmethode für Isonitrile, Angew. Chem. 70 (1958) 702–703, doi:10.1002/ange.19580702213.B. Banerjee, Recent developments on ultrasound-assisted one-pot multicomponent synthesis of biologically relevant heterocycles, Ultrason. Sonochem. 35 (2017) 15–35, doi:10.1016/j.ultsonch.2016.10.010.A. Dömling∗, Recent developments in isocyanide based multicomponent reactions in applied chemistry†, Chem. Rev. 106 (2005) 17–89, doi:10.1021/ CR0505728.I. Pachón-Angona, H. Martin, S. Chhor, M.J. Oset-Gasque, B. Refouvelet, J. Marco-Contelles, L. 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