Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase/monoamine oxidase B inhibitors

<bold>Aim:</bold> Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). <bold>Results:</bold> These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound <bold>A1</bold> possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC50 = 0.054 +/- 0.004 mu M; MAO-B: IC50 = 3.25 +/- 0.20 mu M), moderate inhibitory effects on self-mediated amyloid-beta (A beta) aggregation and antioxidant activity. In addition, compound <bold>A1</bold> exhibited low neurotoxicity. More importantly, compound <bold>A1</bold> showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. <bold>Conclusion:</bold> All results suggest that compound <bold>A1</bold> may become a promising lead of anti-AD drug for further development.