Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

Abstract

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure–activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

Trimethoxycinnamates and Their Cholinesterase Inhibitory Activity

“…It is important to specify that while for AChE inhibition, the position of the substituent on the phenyl ring does not appear to be absolutely crucial (para substituted isomers have only slightly better activity; compare para vs. ortho position of the substituents of compounds 5 and 7 or 4 and 6), for BChE inhibition, it is absolutely the fundamental position of the substituent in the ortho position. The same observations were found recently, e.g., in [53,56,[64][65][66][67][68].…”

“…The ability of all the prepared compounds to inhibit AChE from electric eel (Electrophorus electricus) and BChE from equine serum (both purchased from Sigma, St. Louis, MO, USA) was determined in vitro using a modified Ellman's method, as described previously [49][50][51][52][53].…”

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

“…Moreover, some studies have shown that BuChE may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM) by causing insulin resistance; the latter is considered as one of the major risk factors contributing to AD onset [ 15 , 16 ]. Recently, several new structural scaffolds have been designed, synthesized, and studied as new cholinesterase inhibitors [ 17 , 18 , 19 ].…”

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

“…Human monocytic leukemia THP-1 cells were obtained from the European Collection of Cell Cultures (ECACC, Salisbury, UK) and routinely cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 2% L-glutamine, 1% penicillin, and 1% streptomycin (all from Sigma-Aldrich) at 37 • C with atmosphere containing 5% CO 2 . The tested compounds dissolved at DMSO were added to cells suspended at complete cultivation medium, and the relative cell viability (the ratio between cells treated with compounds and cells treated with DMSO only) was measured by a CCK-8 kit (Sigma-Aldrich) after 24 h, as we described previously [99].…”