Novel N‐allyl/propargyl tetrahydroquinolines: Synthesis via Three‐component Cationic Imino Diels–Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors. (6th June 2016)

• Record Type: Journal Article
• Authors: Rodríguez, Yeray A.; Gutiérrez, Margarita; Ramírez, David; Alzate‐Morales, Jans; Bernal, Cristian C.; Güiza, Fausto M.; Romero Bohórquez, Arnold R.
• Is Part Of: Chemical biology & drug design. Volume 88:Number 4(2016)
• Page Start: 498
• Page End: 510
• Publication Date: 2016-06-06
• Subjects: Alzheimer's disease -- cationic imino Diels–Alder reaction -- cholinesterase inhibitors -- docking and MM‐GBSA simulations -- N‐Allyl/Propargyl tetrahydroquinolines; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12773
• Languages: English
• ISSNs: 1747-0277

Abstract

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 compound4af (IC50 = 72 μ m ) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl‐cholinesterase was exhibited by compound4ae (IC50 = 25.58 μ m ) 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. Abstract : N ‐allyl/propargyltetrahydroquinolines showed inhibitory activity against cholinesterases. Synthesis of tetrahydroquinolines proceeds via a three‐component cationic imino Diels–Alder reaction. The mechanism of enzymatic inhibition was determined by kinetic assays. The computer calculations are consistent with the experimental results.