Synthesis, Biological Evaluation and Molecular Modeling of (E)- 3-Propargylene-1, 3-Dihydro-2H-Indol-2-Ones as Acetyl- and Butyrylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease

The synthesis, pharmacological evaluation and molecular modeling of (E)-3-propargylene-1,3-dihydro-2Hindol- 2-ones, targeting both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are described. In vitro inhibition experiments of AChE and BuChE showed that compound 2, 5 and 12 are able to inhibit the two forms of cholinesterases in the submicromolar range. The most selective inhibitor of EeAChE (acetylcholinesterase, E.C. 3.1.1.7, from Electrophorus electricus) and eqBuChE (butylcholinesterase, E.C. 3.1.1.8, from equine serum) in this series are compound 9 (IC50=0.011 ± 0.018 μM) and compound 14 (IC50=0.12 ± 0.22 μM) respectively. But the substitution at 5- or 6- position of indolones is not generally favored for eqBuChE inhibition. Kinetic studies of the BuChE inhibition suggested that compound 1 and 5 produce a mixed inhibition pattern. The molecular modeling investigation confirmed the result and indicated that π-π stacking interaction is a main contributor to the increase of inhibition efficiency.