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

Abstract

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 µM·L−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 π-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.

Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction

“…Wei Huang and the Gu He research group have reported an impressive hybrid containing ferrocene grafted with the spirooxindole skeleton, which has proven to be a novel MDM2 inhibitor (Figure 1) [27]. Based on this finding, and in continuation of our research program towards the synthesis of a multi-functionalized spirooxindole drug skeleton for drug-research development [28][29][30][31][32], we reported here the novel spirooxindole system appending the ferrocenetriazole-oxindole systems. The molecular and supramolecular features of this novel compound were elucidated, based on the X-ray diffraction of a single crystal, Hirshfeld analysis, and atoms-in-molecules (AIM) calculations.…”

Construction of Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds as Acetylcholinesterase Inhibitors

“…33 Extending our recent efforts on the development of cholinesterase inhibition, Barakat et al reported a new series of spirooxindoles engrafted with the benzo [b]thiophene scaffold, which were found to exhibit moderate potential against AD (Figure 1). 32h, 34 The above reports inspired the investigation of several pharmacophores inside the rigid spirooxindole privileged structure, such as indole and pyrazole scaffolds, which might act as better AChE inhibitors. Several progresses have been devoted toward the synthesis of spirooxindoles recently.…”

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

“…The key step of this strategy is the generation of azomethine ylides (AYs) which then react with electron-deficient ethylene to produce pyrrolidine-spirooxindole with contiguous stereocenters. These pyrrolidine-spirooxindole molecules in particular have shown a panoply of significant pharmaceutical targets and applications, such as MDM2 inhibitors [ 20 , 21 , 22 ], anti-cancer treatment [ 7 , 23 ], AChE inhibitors [ 24 , 25 , 26 ] and prospective activity against SARS-CoV-2 [ 27 ]. Structural modifications have emerged as attractive synthetic targets for researchers.…”