Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds as Potential Cholinesterases Inhibitors: Synthesis, Enzyme Inhibition Assays, and Molecular Modeling Studies
by
Yeray A. Rodríguez Núñez 1
, Margarita Gutíerrez 2,*, Jans Alzate-Morales 3, Francisco Adasme-Carreño 3, Fausto M. Güiza 4, Cristian C. Bernal 4 and Arnold R. Romero Bohórquez 4,*
Yeray A. Rodríguez Núñez 1, Margarita Gutíerrez 2,*, Jans Alzate-Morales 3, Francisco Adasme-Carreño 3, Fausto M. Güiza 4, Cristian C. Bernal 4 and Arnold R. Romero Bohórquez 4,*
1
Laboratorio Síntesis Orgánica, Doctorado en Ciencias Mención Investigación y Desarrollo de Productos Bioactivos, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3460000, Chile
2
Laboratorio Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca 3460000, Chile
3
Center for Bioinformatics, Simulations and Modeling, Faculty of Engineering, University of Talca, 2 Norte 685, Casilla 721, Talca 3460000, Chile
4
Grupo de Investigación de Compuestos Orgánicos de Interés Medicinal (CODEIM), Parque Tecnológico Guatiguará, Universidad Industrial de Santander, A.A. 678, Piedecuesta 681011, Colombia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 5; https://doi.org/10.3390/ijms21010005
Received: 27 November 2019 / Accepted: 4 December 2019 / Published: 18 December 2019
(This article belongs to the Section Molecular Pharmacology)
A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of all compounds was tested. Enzyme inhibition assays showed that some hybrids exhibited significant potency to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Especially, the hybrid compound 5n presented the more effective inhibition against AChE (4.24 µM) with an acceptable selectivity index versus BChE (SI: 5.19), while compound 6aa exhibited the greatest inhibition activity on BChE (3.97 µM) and a significant selectivity index against AChE (SI: 0.04). Kinetic studies were carried out for compounds with greater inhibitory activity of cholinesterases. Structure–activity relationships of the molecular hybrids were analyzed, through computational models using a molecular cross-docking algorithm and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy approach, which indicated a good correlation between the experimental inhibition values and the predicted free binding energy.
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Keywords:
Alzheimer’s disease; cholinesterase inhibitors; cross-docking and MM/GBSA free binding energy; hybrid compounds
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MDPI and ACS Style
Rodríguez Núñez, Y.A.; Gutíerrez, M.; Alzate-Morales, J.; Adasme-Carreño, F.; Güiza, F.M.; Bernal, C.C.; Bohórquez, A.R.R. Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds as Potential Cholinesterases Inhibitors: Synthesis, Enzyme Inhibition Assays, and Molecular Modeling Studies. Int. J. Mol. Sci. 2020, 21, 5.
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