article · ChemistrySelect
A new series of spirooxindole analogues tethered to a pyrazole scaffold has been synthesised through a [3+2] cycloaddition reaction. The chemical structure of the starting chalcone was confirmed using single crystal X-ray diffraction analysis. The cycloaddition proceeds via a polar, one-step mechanism driven by supernucleophilic azomethine ylides and electrophilic ethylenes. The resulting compounds were assessed for neuroprotective potential by measuring their inhibition of the acetylcholinesterase enzyme through Ellman's method. Among the tested molecules, three candidates demonstrated the strongest inhibitory effects, with compound 9w showing the highest potency, followed by compounds 9e and 9x. Structure-activity observations revealed that adding a nitro group at the fifth position of isatin alongside sarcosine was crucial for achieving maximal inhibitory performance. Additionally, molecular docking simulations examined how these active molecules bind within the human acetylcholinesterase active site.
Acetylcholinesterase inhibitors are central to managing neurodegenerative conditions by preserving neurotransmitter levels. By establishing a synthesis route for novel spirooxindole-pyrazole compounds and identifying specific chemical modifications that enhance enzyme inhibition, this laboratory work provides targeted molecular leads. Understanding how these chemical structures interact with the human enzyme assists researchers in refining potential therapeutics for neurodegenerative disorders.
This work identifies early-stage chemical candidates capable of inhibiting human acetylcholinesterase, a target relevant to neurodegenerative disease therapeutics. The research represents early laboratory discovery, validated only through in vitro enzyme assays and computational docking. Potential beneficiaries include pharmaceutical developers seeking new molecular scaffolds. Substantial preclinical validation, toxicology screening, and in vivo efficacy testing remain necessary before these compounds could approach practical pharmaceutical development.
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Abstract A new series of spirooxindole analogs tethered pyrazole scaffold constructed via [3+2] cycloaddition (32CA) reaction starting from the new chalcone named ( E )‐3‐(5‐chloro‐3‐methyl‐1‐phenyl‐1 H ‐pyrazol‐4‐yl)‐1‐(5‐methyl‐1‐phenyl‐1 H ‐pyrazol‐4‐yl)prop‐2‐en‐1‐one which confirmed by single crystal X‐ray diffraction analysis. Synthesized spirooxindole analogs were evaluated for their neuroprotection through the inhibition of acetylcholine esterase enzyme using Ellman's method. Compounds 9 w , 9 e and 9 x showed the strongest acetylcholine esterase inhibition (AChEI) with IC 50 values of 5.7, 7.8 and 8.3 μM, respectively. Obviously, the incorporation of NO 2 group into isatin 5t h position and N ‐methylglycine (sarcosine) play a crucial role for the activity which lead to compound 9 w had the most potent inhibitory activity with IC 50 value of 5.7 μM. Molecular docking was used to study their interaction with the active site of hAChE. These 32CA reactions takes place via a one‐step mechanism with a high polar character as a consequence of the supernucleophilic character of azomethine yildes and the strong electrophilic character of ethylenes.
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DOI: 10.1002/slct.202103255
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