Abstract

Background: Alzheimer’s disease (AD) is a complex neurodegenerative condition for which a single protein-targeting medication is not enough to provide a cure. All the medications now available for AD are palliative. FDA has approved five medications for the treatment of AD, i.e., tacrine, donepezil, galantamine, rivastigmine, and memantine. Due to hepatotoxicity, tacrine is no longer utilized in clinical practice. Due to the lack of therapeutic efficiency of single-target medications and the multifaceted etiology of AD, multitarget-directed ligands have been developed.

Objectives: The present research focused on incorporating a flavone nucleus into the amino group of 9-amino acridine nucleus to make it an acetylcholinesterase (AChE) and butyryl cholinesterase inhibitor (BuChE) with less toxicity.

Methods: We designed and synthesized ten flavone-substituted acridine derivatives and evaluated them for in vitro AChE and BuChE inhibitory activity. Molecular modeling studies were conducted using AutoDock Vina with hAChE (PDB ID: 4EY7) and hBuChE (PDB ID: 4TPK). The toxicity profile of the most active novel compound tested on zebrafish larvae for determining the liver and cardiac toxicity and LD50 value of the compound were determined.

Results: In vitro AChE and BuChE inhibitory study by Ellman assay showed acceptable results. The compound AF2 showed the highest activity with an IC₅₀ value of 0.99 ± 0.1 μM for AChE and 1.78 ± 0.19 for BuChE. The in vivo acute toxicity studies conducted on zebra fish larvae did not show cardiac and hepatotoxicity, and the LD₅₀ value was found to be 1000 μL.

Conclusion: The results highlighted the AChE and BuChE inhibitory effects of the novel acridine- flavone hybrids, and they can be promising multitarget-directed ligands for AD.

Keywords: Acridine, acetylcholinesterase, alzheimer’s disease, flavone, butyrylcholinesterase, molecular docking.

Graphical Abstract