Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds as Potential Cholinesterases Inhibitors: Synthesis, Enzyme Inhibition Assays, and Molecular Modeling Studies

• Published in: International journal of molecular sciences Vol. 21; no. 1; p. 5
• Main Authors: Rodríguez Núñez, Yeray A, Gutíerrez, Margarita, Alzate-Morales, Jans, Adasme-Carreño, Francisco, Güiza, Fausto M, Bernal, Cristian C, Bohórquez, Arnold R Romero
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18-12-2019; MDPI
• Subjects: Acetylcholinesterase; Acetylcholinesterase - chemistry; Alzheimer's disease; Binding energy; Binding Sites; Catalytic Domain; Chemistry Techniques, Synthetic; Cholinergics; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Chromatography; Computer applications; Cycloaddition; Drugs; Enzyme Activation - drug effects; Enzymes; Free energy; Humans; Hybrids; Hydrogen Bonding; Isoxazoles - chemistry; Kinetics; Logistics; Mathematical models; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular modelling; Molecular Structure; Protein Binding; Quinolines - chemistry; Selectivity; Structure-Activity Relationship; cholinesterase inhibitors; cross-docking and MM/GBSA free binding energy; Alzheimer’s disease; hybrid compounds
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010005

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
-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.