a b s t r a c tRivastigmine 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 p-p interactions and (c) possible CH/p interactions between the benzylic methyl group and the Nmethyl groups of the inhibitor and W82 of the enzyme.

Microsomal prostaglandin E(2) synthase (mPGES-1) has been identified recently as a novel target for treating pain and inflammation. The aim of this study is to understand the binding affinities of reported inhibitors for mPGES-1 and further to design potential new mPGES-1 inhibitors. 3D-QSAR-CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) - techniques were employed on a series of indole derivatives that act as selective mPGES-1 inhibitors. The lowest energy conformer of the most active compound obtained from systematic conformational search was used as a template for the alignment of 32 compounds. The models obtained were used to predict the activities of the test set of eight compounds, and the predicted values were in good agreement with the experimental results. The 3D-QSAR models derived from the training set of 24 compounds were all statistically significant (CoMFA; q (2) = 0.89, r (2) = 0.95, [Formula: see text], [Formula: see text] and CoMSIA; q (2) = 0.84, r (2) = 0.93, [Formula: see text], [Formula: see text]). Contour plots generated for the CoMFA and CoMSIA models reveal useful clues for improving the activity of mPGES-1 inhibitors. In particular, substitutions of an electronegative fluorine atom or a bulky hydrophilic phenoxy group at the meta or para positions of the biphenyl rings might improve inhibitory activity. A plausible binding mode between the ligands and mPGES-1 is also proposed.

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.

a b s t r a c tA 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 IC 50 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 IC 50 of 89.5 lM for EeAChE and 153.8 lM for EqBuChE, (2a) was identified as a second hit with an IC 50 of 108.4 lM (EeAChE) and 277.8 lM (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.