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 (AChE) and butyryl-cholinesterase (BChE) 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 AChE despite its poor selectivity (SI= 2), while the best inhibitory activity on BChE 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 AChE and BChE active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.

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N-allyl/propargyl tetrahydroquinolines 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.

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