Design and synthesis of novel chalcone derivatives and evaluation of their inhibitory activities against acetylcholinesterase

Abstract

According to the cholinergic hypothesis, an increase in the acetylcholine level in Alzheimer's disease patients relatively slows down the symptoms of the disease. The most commonly used drug, donepezil, is a cholinesterase inhibitor. In this study, 12 new chalcones (2a–l) were designed and synthesized. In biological activity studies, the acetylcholinesterase (AChE) and butyrylcholinesterase inhibitory potentials of all compounds were evaluated using the in vitro Ellman method. The biological evaluation showed that compounds 2d, 2f, 2j, and 2l displayed significant activity against AChE. The compounds 2d, 2f, 2j, and 2l displayed IC50 values of 0.042, 0.024, 0.053, and 0.033 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also displayed significant inhibition of AChE. The inhibitory activities of these compounds for β‐amyloid plaque aggregation were investigated. The enzyme kinetic study was performed to observe the effect of the most active compound 2f on the substrate–enzyme relationship, and a mixed‐type inhibition of AchE was determined. Further, docking simulation also revealed that these compounds (2d, 2f, 2j, and 2l) interacted with the enzyme active site in a similar manner to donepezil. The most active derivative, compound 2f, interacted with the amino acids Trp286, Phe295, Tyr341, Trp86, and Glu202.

N‐Substituted Arylidene‐3‐(Methylsulfonyl)‐2‐Oxoimidazolidine‐1‐Carbohydrazide as Cholinesterase Inhibitors: Design, Synthesis, and Molecular Docking Study

“…The phenyl ring in the structure exhibited two π‐π interactions with the phenyl rings of Trp286 and Tyr341. Especially the interaction with Trp286 was the strongest interaction of the donepezil molecule in the peripheral anionic region [24–28] . The observation of this interaction in the most effective derivative 3j was a very important finding in terms of the explanation of binding this compound to the AChE enzyme.…”

“…In this study β-amyloid aggregation inhibition activities of compounds 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3q, 3v, 3w and 3x showed high inhibitory activity against the AChE enzyme were carried out using the 'β-Amyloid 1-42 (Aβ42) Ligand Screening Assay (BioVision, Milpitas, CA, USA)' kit based on the fluorometric method. [24,25] The test kit, based on the fluorometric method, was used following the recommended procedure. If an Aβ42 ligand is present, this reaction is inhibited/destroyed, thereby reducing or eliminating fluorescence.…”

“…In Vitro ChE Enzymes Inhibition Assay AChE and BChE inhibitory activities of the synthesized compounds were assessed using the modified Ellman method, as described in the previous studies published by our team. [24,25,27,28,31,32] β-Amyloid 1-42 (Aβ42) Inhibitor Screening Assays…”

“…The experimental procedure was based on the 'β-Amyloid 1-42 (Aβ42) Ligand Screening Assay' kit (BioVision, Milpitas, CA, USA) protocol based on the fluorometric method. [24,25]…”

Design, synthesis, acetylcholinesterase, butyrylcholinesterase, and amyloid‐β aggregation inhibition studies of substituted 4,4ʹ‐diimine/4,4ʹ‐diazobiphenyl derivatives

“…It is suggested that small molecules with planar ring scaffolds as terminal groups can intercalate between Aβaggregates. [22][23][24][25] On the other hand, Wangs and coworkers designed symmetrical molecules having biphenyl scaffolds by using structurebased virtual screening and high throughput screening. [26] These compounds having biphenyl scaffolds were tested for inhibitory activity against cholinesterase (ChE) and it was found that they exhibited AChE inhibition at the micromolar level.…”