Synthesis and Evaluation of Acetylcholinesterase Inhibitory Activity of Chromone Derivatives

Abstract

Alzheimer's disease (AD) is considered as one of the biggest global public burden. An estimate 30% of the world's population over age of 65 are affected by AD. Nowadays, six hundred thousand of Thai people were suffered from this disease. Cause of this disease is proposed to be associated with reduced level of the neurotransmitter acetylcholine (ACh). Cholinesterase, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), destroy ACh through hydrolysis. Cholinesterase inhibitors (ChEl) portray the main group of drugs currently used for the treatment of AD such as donepezil, tacrine and galanthamine. In this research, 12 chromone derivatives were designed and synthesized using compound N-(4-((2-methoxybenzyl)ethyl)amino)butyl)-5-hydroxy-4-oxo-4H-chromene- 2-carboxamide (A) and donepezil were used as references. Structure of target compounds was characterized with IR, 'H-NMR, I3C-NMR spectroscopy and mass spectrometry. Cholinesterase inhibitory activity of chromone derivatives (7-18) was evaluated using the Ellman's method. In addition, the kinetic study for characterization of AChE inhibition and molecular docking studies demonstrated interactions between enzyme and ligand were evaluated by using computer program. Chromone derivatives (7-18) showed percent inhibition of AChE and BChE higher than 50% at 100 M. Most of the synthesized compound exhibited potent AChE inhibitory activities at the nanomolar to micromolar range (IC50 0.09-9.16 M) and demonstrated weak BChE inhibitory activities at the micromolar range (IC50 12.09-44.56 HM). Compound 14 was the most potent AChEl, it exerted ICso in nanomolar range, higher activity than the clinical used drug tacrine. Enzyme kinetic study and molecutar docking revealed that compound 14 was uncompetitive inhibitor and dual-binding site inhibitor.