Abstract
Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8andCD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). CompoundCD8most potently inhibited MAO-B with an IC(50)value of 0.026 mu M, followed byCD10andCD3(1.54 and 1.68 mu M, respectively).CD8potently and non-selectively inhibited MAO-A (IC(50)value of 0.023 mu M). On the other hand,CD10andCD8inhibited AChE with IC(50)values of 5.40 and 9.57 mu M, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K(i)values ofCD8for MAO-A and MAO-B were 0.018 and 0.0019 mu M, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate thatCD8is a potent non-selective MAO inhibitor, andCD10is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest thatCD8andCD10be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.