ABSTRACT
The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aß1-42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer's disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1-22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman's colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aß1-42 aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC50 values of 1.08 and 1.09 µM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aß1-42 aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Drug Design , Indenes/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/prevention & control , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Indenes/chemical synthesis , Indenes/chemistry , Kinetics , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Structure-Activity RelationshipABSTRACT
Amyloid beta (Aß) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimer's disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Aß with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and ß1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti-Alzheimer's agents.
