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

Abstract

Twenty-five new hits of spirooxindole analogs 8a-y engrafted with indole and pyrazole scaffolds were designed and constructed via a [3+2]cycloaddition (32CA) reaction starting from three components: new chalcone-based indole and pyrazole scaffolds 5a-d, substituted isatins 6a-c, and secondary amines 7a-d. The potency of the compounds were assessed in modulating cholinesterase (AChE) activity using Ellman's method. Compounds 8i and 8y showed the strongest acetylcholine esterase inhibition (AChEI) with IC₅₀ values of 24.1 and 27.8 μM, respectively. Molecular docking was used to study their interaction with the active site of hAChE.

Figure 1

Significant acetylcholinesterase (AChE) inhibitory activity of representative spirooxindole analogues.

Scheme 1. Synthesis of the Chalcone Engrafted with Indole and Pyrazole Scaffolds 5a–d

Scheme 2. Synthesis of the Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds 8a–y

Scheme 3. Proposed Approach for the [3 + 2] Cycloaddition Reaction, Explaining the Regio- and Diastereoselective Synthesis

Figure 2

Atom numbering and thermal ellipsoids at a 30% probability level for 8c.

Figure 3

Hydrogen bond contacts (left) and packing of molecular units via hydrogen bonding interactions (right).

Figure 4

Donepezil (Red) docked in the active site of ACHE (4EY7) and overlaid with cocrystallized ligand (Green) RMSD = 0.39.

Figure 5

8i docked in the active site of ACHE (4EY7) and corresponding two-dimensional (2D) presentation. The H-bond is represented by green dotted lines, hydrophobic interactions are represented by magenta dotted lines, and Pi-sulfur interaction is represented by orange dotted lines.

Figure 6

8y docked in the active site of ACHE (4EY7) and corresponding 2D presentation. The H-bond is represented by green dotted lines, hydrophobic interactions are represented by magenta dotted lines, and Pi-sulfur interaction is represented by orange dotted lines.

Figure 7

8h docked in the active site of ACHE (4EY7) and corresponding 2D presentation. The H-bond is represented by green dotted lines, hydrophobic interactions are represented by magenta dotted lines, and Pi-sulfur interaction is represented by orange dotted lines.