Indolinone-based acetylcholinesterase inhibitors: synthesis, biological activity and molecular modeling

A series of indolinone-based compounds bearing benzylpyridinium moiety was designed as dual-binding inhibitors of acetylcholinesterase (AChE). The target compounds 3a-u were synthesized by condensation of oxindole and pyridin-4-carbalehyde, and subsequent N-benzylation. The anti-cholinesterase activity evaluation of synthesized compounds revealed that most of them had very potent inhibitory activity against AChE, superior to standard drug donepezil. Particularly, 2-chlorobenzyl derivative 3c was the most potent compound against AChE with IC50 value of 0.44 nM, being 32-fold more potent than donepezil. Also, most of compounds were more potent than standard drug donepezil against butyrylcholinesterase (BuChE). Docking study revealed that the hydrophobic aromatic part (indoline) of representative compound 3c binds to the PAS and the N-benzylpyridinium residue binds to the CAS of AChE.