graveoline and Alzheimer-Disease

Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and unsatisfactory long-term treatment effect. Recent studies have shown that butyrylcholinesterase (BuChE) inhibitors or double acetyl and butyryl cholinesterase inhibitors have better curative effects on AD, and the side effects are lower than those of specific AChE inhibitors. Dual target cholinesterase inhibitors have become a new hotspot in the research of anti-AD drugs. Herein, the synthesis and bioactivities of BuChE inhibitors were reviewed.

Topics: Acridines; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Methoxsalen; Structure-Activity Relationship

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Hep G2 Cells; Horses; Humans; Male; Methoxsalen; Mice; Molecular Structure; PC12 Cells; Peptide Fragments; Rats; Structure-Activity Relationship

This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n = 3) and the terminal amino was piperidine, compound 5c showed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y.

Topics: Acetylcholinesterase; Alzheimer Disease; Binding Sites; Butyrylcholinesterase; Cell Line; Cell Proliferation; Cholinesterase Inhibitors; Humans; Methoxsalen; Models, Molecular; Molecular Docking Simulation; Structure-Activity Relationship