Effect on Acetylcholinesterase and Anti-oxidant Activity of Synthetic Chalcones having a Good Predicted Pharmacokinetic Profile

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 13; no. 7; p. 654
• Main Authors: Sakata, Renata P, Figueiro, Micheli, Kawano, Daniel F, Almeida, Wanda P
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2017
• Subjects: Acetylcholinesterase - chemistry; Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - metabolism; Antioxidants - pharmacokinetics; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Catalytic Domain; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - metabolism; Chalcones - pharmacokinetics; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - pharmacokinetics; Cytochrome P-450 CYP3A - metabolism; Gastrointestinal Absorption - drug effects; Kinetics; Molecular Docking Simulation; Tacrine - pharmacokinetics; Torpedo; inhibitors; brain neurons; molecular docking; Acetylcholinesterase; assay; Alzheimer's disease
• ISSN: 1875-6638
• DOI: 10.2174/1573406413666170525125730

Acetylcholinesterase (AChE) is an important target in the development of drug to treat Alzheimer's disease (AD). In this work, we investigated the effect of twenty-two synthesized chalcones on AChE activity.
This work is aimed to synthesize and evaluate the effect of chalcones on the AChE activity, as well as anti-oxidant activity and predict their pharmacokinetic profile.
Chalcones were synthesized through a Claisen-Schmidt condensation and their inhibitory effect on the AChE was evaluated by the Elmann's colorimetric method. To determine the anti-oxidant activity the DPPH radical scavenging method was chosen.
We found that all chalcones inhibit this activity, with IC50 values ranging from 0.008 to 4.8 µM. We selected the most active compound 19 with an IC50 value of 0.008 µM for a kinetic study demonstrating a competitive inhibition mode. Molecular docking simulations showed a good interaction between 19 and the active site of AChE. Considering the prediction of pharmacokinetic parameters being a useful tool for selecting potential drug candidates, our study results suggest that the majority of chalcones, including the most active one, have a promising pharmacokinetic profile and blood-brain barrier permeability. The involvement of reactive oxygen species (ROS) in AD-related events has encouraged us to evaluate these chalcones as radical scavengers.
We have found that compound 19 is a potent AChE inhibitor, and based on kinetic studies, it acts as a competitive inhibitor.