Kia_2014_Bioorg.Med.Chem_22_1318

One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC(5)(0) values of 2.36-9.43 muM. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC(5)(0) values of lower than 10 muM displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC(5)(0) values of 7.44-19.12 muM. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC(5)(0) values of 2.35 and 3.21 muM, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated Ki values of 2.01 and 6.76 muM, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC(5)(0) values and free binding energy values of the synthesized compounds docked into the active site of the enzymes.