Synthesis of Novel Chalcones as Acetylcholinesterase Inhibitors

Abstract

Abstract:A new series of benzylaminochalcone derivatives with different substituents on ring B were synthesized and evaluated as inhibitors of acetylcholinesterase. The study is aimed at identification of novel benzylaminochalcones capable of blocking acetylcholinesterase activity for further development of an approach to Alzheimer's disease treatment. These compounds were produced in moderate to good yields via Claisen-Schmidt condensation and subjected to an in vitro acetylcholinesterase inhibition assay, using Ellman's method. The in silico docking procedure was also employed to identify molecular interactions between the chalcone compounds and the enzyme. Compounds with ring B bearing pyridin-4-yl, 4-nitrophenyl, 4-chlorophenyl and 3,4-dimethoxyphenyl moieties were discovered to exhibit significant inhibitory activities against acetylcholinesterase, with IC 50 values ranging from 23 to 39 µM. The molecular modeling studies are consistent with the hypothesis that benzylaminochalcones could exert their effects as dual-binding-site acetylcholinesterase inhibitors, which might simultaneously enhance cholinergic neurotransmission and inhibit β-amyloid aggregation through binding to both catalytic and peripheral sites of the enzyme. These derivatives could be further developed to provide novel leads for the discovery of new anti-Alzheimer drugs in the future.

Species of the Genus Salix L.: Biochemical Screening and Molecular Docking Approach to Potential Acetylcholinesterase Inhibitors

“…In order to get insight into the interactions of these ligands with the active site of AChE has a narrow 20 Å gorge with two binding sites: the catalytic active site at the bottom of the structure and the peripheral anionic site (PAS) near the entrance of the gorge. Consequently, ligands that bind to either one or two of the sites represent promising inhibitors of AChE in treatment of AD [43].…”

“…Active site of the AChE enzyme with chlorogenic acid: (a) 3D view; (b) 2D view.AChE has a narrow 20 Å gorge with two binding sites: the catalytic active site at the bottom of the structure and the peripheral anionic site (PAS) near the entrance of the gorge. Consequently, ligands that bind to either one or two of the sites represent promising inhibitors of AChE in treatment of AD[43].Epicatechin showed several hydrogen bonds with prominent amino acid residues of the PAS anionic subsite of AChE, namely Asp 74, Tyr 124 and Tyr 341, while van der Waals interaction with Trp 286. Hydrogen bond interactions of -OH groups of phenyl moiety with Asp 74 carboxylate group are established.…”

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

“…One of the neurodegenerative diseases in which oxidative stress has been regarded as one of the underlying causes is Alzheimer's disease (AD) [10], being that this disease is the most frequent cause of dementia in elderly people [11]. As the cholinergic deficit is heavily related to the disease progression, inhibitors of the enzyme acetylcholinesterase (AChEI) are potential drugs for the treatment of AD patients [12].…”

Computer-aided Design of Chalcone Derivatives as Lead Compounds Targeting Acetylcholinesterase

“…Promising compounds to be developed as AChE inhibitor were chalcone derivatives (Sukumaran et al, 2016;Tran et al, 2016). Chalcones or 1,3-diphenyl-2-propene-1-one can be obtained both from the plants (Abdelwahab, 2013;Adewusi et al, 2010) and from the synthetic way due to condensation reaction between substituted aromatic aldehyde with substituted acetophenones in alkaline condition (Jayapal and Sreedhar, 2010).…”