Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

A series of new oxindole-based spiro-heterocycles bearing the benzo[b]thiophene motif were synthesized via a 1,3-dipolar cycloaddition reaction and their acetylcholinesterase (AChE) inhibitory activity was evaluated. All the synthesized compounds exhibited moderate inhibitory activities against AChE, while IIc was found to be the most active analog with an IC50 value of 20,840 &micro
M&middot
L&minus
1. Its molecular structure was a 5-chloro-substituted oxindole bearing benzo[b]thiophene and octahydroindole moieties. Based on molecular docking studies, IIc was strongly bound to the catalytic and peripheral anionic sites of the protein through hydrophilic, hydrophobic, and &pi
stacking interactions with Asp74, Trp86, Tyr124, Ser125, Glu202, Ser203, Trp236, Trp286, Phe297, Tyr337, and Tyr341. These interactions also indicated that the multiplicity of the IIc aromatic core significantly favored its activity.