Synthesis of Spirooxindole Analogs Tethered Pyrazole Scaffold as Acetylcholinesterase Inhibitors

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-1H-pyrazol-4-yl)-1-(5-methyl-1-phenyl-1H-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 IC50 values of 5.7, 7.8 and 8.3 μM, respectively. Obviously, the incorporation of NO2 group into isatin 5th 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 IC50 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.