Novel indanone-chalcone esters with potential anti-Alzheimer effects designed using hybridization and bioisosteric replacement approaches

Using molecular hybridization and bioisosteric replacement approaches, novel agents with potential use for the treatment of Alzheimer’s disease (AD) were developed based on the structure of donepezil. A series of 14 indanone-chalcones bearing ester group were designed, synthesized, and then characterized using variety of methods. All target compounds showed moderate acetylcholinesterase (AChE) inhibitory potencies and among them, the most active compound 8e exhibited inhibitory activity with IC₅₀ value of 18.7 µM against AChE. Also, Aβ_1–40 aggregation inhibitory activities of the synthesized compounds were evaluated, and the results showed that compound 8h was able to inhibit Aβ_1–40 aggregation by 81.6%. The results of docking studies revealed that some of compounds fits well into the binding site of AChE. The most active AChE inhibiting derivative 8e has close physico-chemical properties to donepezil (reference compound) and passed more drug likeness filters relative to the reference compound. Collectively, the current study provides insight for designing drug size molecules with ester group to target acetylcholinesterase in the process of developing new active compounds for AD. Graphical Abstract: [Figure not available: see fulltext.].