title: Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.
abstract: New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 μm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 μm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.
authors.affiliation: Laboratorio Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, 3460000, Chile.
authors.forename: Yeray A
authors.initials: YA
authors.lastname: Rodríguez
authors.affiliation: Laboratorio Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, 3460000, Chile. mgutierrez@utalca.cl.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gutiérrez
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, 3460000, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Ramírez
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, 3460000, Chile.
authors.forename: Jans
authors.initials: J
authors.lastname: Alzate-Morales
authors.affiliation: Grupo de Investigación de Compuestos Orgánicos de Interés Medicinal (CODEIM), Parque Tecnológico Guatiguará, Universidad Industrial de Santander, A.A. 678, Piedecuesta, Colombia.
authors.forename: Cristian C
authors.initials: CC
authors.lastname: Bernal
authors.affiliation: Grupo de Investigación de Compuestos Orgánicos de Interés Medicinal (CODEIM), Parque Tecnológico Guatiguará, Universidad Industrial de Santander, A.A. 678, Piedecuesta, Colombia.
authors.forename: Fausto M
authors.initials: FM
authors.lastname: Güiza
authors.affiliation: Grupo de Investigación de Compuestos Orgánicos de Interés Medicinal (CODEIM), Parque Tecnológico Guatiguará, Universidad Industrial de Santander, A.A. 678, Piedecuesta, Colombia. arafrom@uis.edu.co.
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Romero Bohórquez
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002412:Cations; D002794:Choline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D061565:Cycloaddition Reaction; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D002412:Cations; D002800:Cholinesterase Inhibitors; D011804:Quinolines; C000603143:propargylcholine; C037219:quinoline; D002794:Choline
keywords: Alzheimer's disease; N-Allyl/Propargyl tetrahydroquinolines; cationic imino Diels-Alder reaction; cholinesterase inhibitors; docking and MM-GBSA simulations