Design Synthesis and Evaluation of Tacrine-flavone Hybrids as Multifunctional Cholinesterase Inhibitors for Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. The multifactorial etiology of AD has led to the design of multitarget directed ligands (MTDL) for AD. Tacrine an acetylcholinesterase (AChE) inhibitor was the first FDA approved drug for AD but is discontinued due to hepatotoxicity.

Objective: Present research focused on incorporating a flavone to the tacrine nucleus to enhance the anti-Alzheimer's property of the tacrine with the synergistic effect of flavone which is a very good antioxidant. It is expected that the antioxidant property and hepatoprotective nature of flavones will reduce the hepatotoxic side effect of tacrine.

Methods: We designed and synthesized ten flavone substituted tacrine derivatives and evaluated for in vitro AChE and BuChE inhibitoy activity by modified Ellman's method using eeAChE and eqBuChE. In vitro antioxidant activity was studied by DPPH radical scavenging assay. Molecular modeling studies were conducted in Schrodinger and AutoDock Vina with TcAChE(PDB ID:1H23),hAChE(PDB ID:4EY7) and hBuChE(PDB ID:4TPK).

Results: All the compounds exhibited potent inhibitory effect on AChE and BuChE with IC50 values in μM concentration. The compounds exhibited very good antioxidant activity in DPPH radical scavenging assay. Among the compounds the compound AF1 showed highest activity with IC50 value of 0.93 μM for AChE and 1.48 μM for BuChE and also showed significant antioxidant activity (2.6 nM). A correlation graph was plotted for IC 50 values vs Dock score and the results are promising with r2 values of 0.62 and 0.73 for AChE and BuChE inhibition respectively which proved the reliability of docking approaches.

Conclusion: The results highlighted the multifunctional nature of the novel Tacrine-Flavone hybrids and they may be promising MTDL for AD.