New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via pi-pi interactions and (c) possible CH/pi interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.

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 μM), a library of 31 analogues of 3-substituted-3-hydroxyoxindoles was synthesized and screened for both acetylcholinesterase (AChE) and BuChE activity. Our bioassays 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 μM. 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 μM 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 μM for BuChE.