Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives

Abstract

Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound 10 provided a desired balance of AChE and hMAO-B inhibition activities, with IC₅₀ value of 3.94 and 3.44 μM, respectively. Further studies revealed that compound 10 was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that 10 was a promising dual functional agent for the treatment of AD.

• Alzheimer’s disease
• cholinesterase inhibitors
• homoisoflavonoid derivatives
• MAO inhibitors

Declaration of interest

The authors declare no conflicts of interest.

We thank the National Natural Science Foundation of China (No. 21302235, 20972198), the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation (2011A060901014) and Ph.D. Programs Foundation of Ministry of Education of China (20120171120045) for financial support of this study.

Supplementary material available online

Supporting Information.