Design, Synthesis and Bioassays of 3-Substituted-3-Hydroxyoxindoles for Cholinesterase Inhibition

Based on the positive bioassay results of the known oxindole hit compound rac-1-benzyl-3-hydroxy-3-phenylindolin-2-one which showed significant inhibition of butyrylcholinesterase (BuChE) (IC50= 7.41 mu M), a library of 31 analogues of 3-substituted-3-hydroxyoxindoles was synthesized and screened for both acetylcholinesterase (AChE) and BuChE activity. Our bio-assays revealed that some of the new compounds exhibited moderate inhibition of eel AChE (EeAChE) and very good inhibition of equine serum BuChE (EqBuChE) with a best IC50 of 1.02 mu M. On the basis of these results, the lead compound 1-((1-benzylpiperidin-4-yl)methyl)-3-hydroxy-3-phenylindolin-2-one was designed, which was shown to interact well with the enzymes active sites by molecular docking, was synthesized and upon bioassay gave an IC50 of 6.61 mu M for BuChE. Interestingly, when we separated rac-benzyl-3-hydroxy-3-phenylindolin-2-one into the individual enantiomers (R)-and (S)-benzyl-3-hydroxy-3-phenylindolin-2-one it was the latter enantiomer that gave the best IC50 of 6.19 mu M for BuChE.