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

Abstract

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.

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

“…this compound was tested for inhibition of both AChE ( Electrophorus electricus (eel) Ee AChE) and BuChE (equine, Eq BuChE) and was shown to be more selective towards Eq BuChE than Ee AChE with an IC 50 of 10.08 μM whilst it gave an IC 50 of 124.20 μM for Ee AChE. The structure of Ee AChE was discussed in our previous report …”

“…Ee AChE possesses the catalytic triad S203, E334 and H447, the aromatic residues F295 and F297, that define an acetylcholine‐specific acyl pocket, the tryptophan residue W86, which interacts with the choline moiety in the anionic binding site, G121 and G122 are considered to be part of the oxyanion hole ‐ as well as the 14 aromatic residues lining the walls of a deep narrow gorge of about 20 Å (Fig. 2) . All 14 amino acids in the aromatic gorge are highly conserved across different species …”

“…In the case of AChE, there was a H‐bond formed in the active site with the hydroxyl group O1 of 1 and with the OH group of W86 (2.90 Å), and another H‐Bond formed between the carbonyl oxygen of 1 and the OH group of Y341 (2.85 Å). As the AChE active site is known to be hydrophobic, it was observed that the benzyl group of 1 formed some π‐π stacking hydrophobic interactions with residues W86 and Y341. In the case of F297 (acyl binding pocket) there was a distinct edge‐to‐face interaction with the benzyl phenyl group.…”

Construction of Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds as Acetylcholinesterase Inhibitors

“…On the other hand, compounds 8h and 8y showed most of their interactions with amino acids located at the entrance of the gorge. For example, compound 8i was able to interact with amino acids in diverse sites in the enzyme such as TRP-86 and TYR-337 in the anionic site, Ser-203 and HIS-447 in the catalytic site, PHE-295 and PHE-297 in the acyl binding site, and formed 2 hydrogen bonds with SER-125 and GLU-202, as depicted in Figure , these interactions are well reported to be important for achieving good inhibitory activity …”

Sequential alcohol oxidation/putative homo Claisen–Tishchenko-type reaction to give esters: a key process in accessing novel biologically active lactone macrocycles

“…Overall these compounds are much better inhibitors for AChE than for BuChE which makes sense when one considers the tighter active site that exists in the case of the former. 16 …”