Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti-AD Lead Compound.

Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins was chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1-3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, β amyloid (Aβ) aggregation, and metal ions were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1-3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC 50 =11.15 μM). Compound 1-3 could also selectively chelate with Cu 2+ and Al 3+ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1-3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1-3 could be promising MTDLs applied as anti-AD candidate drugs.