article · ACS Omega
Twenty-five novel spirooxindole analogues incorporating indole and pyrazole motifs were synthesised using a three-component cycloaddition reaction. The chemical construction combined chalcone-based indole and pyrazole derivatives, substituted isatins, and secondary amines. Following synthesis, the inhibitory potency of these compounds against acetylcholinesterase was evaluated using the standard Ellman assay. Among the series, two candidates, designated 8i and 8y, demonstrated the most pronounced enzyme-inhibiting capabilities, yielding half-maximal inhibitory concentration values of 24.1 and 27.8 micromolar, respectively. In addition to laboratory testing, molecular docking simulations were conducted to examine the specific binding interactions of these leading molecules within the active site of human acetylcholinesterase. These findings outline an efficient synthetic route to new enzyme-targeting chemical scaffolds.
Acetylcholinesterase inhibitors play an important role in the study and management of neurodegenerative disorders by preventing the breakdown of neurotransmitters. Developing new chemical scaffolds that interact with this enzyme offers valuable reference points for medicinal chemists seeking alternative molecular starting points for future drug discovery efforts.
This research is at an early experimental stage, focusing on initial synthesis, enzyme assays, and computational docking. The findings could potentially assist pharmaceutical discovery teams seeking new chemical starting points for neurodegenerative disease research. Moving toward practical application would require substantial further development, including structure optimisation to improve potency, cellular assays, and preclinical pharmacokinetic and safety evaluations.
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Twenty-five new hits of spirooxindole analogs <b>8a-y</b> engrafted with indole and pyrazole scaffolds were designed and constructed <i>via</i> a [3+2]cycloaddition (32CA) reaction starting from three components: new chalcone-based indole and pyrazole scaffolds <b>5a-d</b>, substituted isatins <b>6a-c</b>, and secondary amines <b>7a-d</b>. The potency of the compounds were assessed in modulating cholinesterase (AChE) activity using Ellman's method. Compounds <b>8i</b> and <b>8y</b> showed the strongest acetylcholine esterase inhibition (AChEI) with IC<sub>50</sub> values of 24.1 and 27.8 μM, respectively. Molecular docking was used to study their interaction with the active site of hAChE.
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DOI: 10.1021/acsomega.1c03978
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