Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer’s disease

摘要

Graphical abstract Display Omitted Abstract With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer’s disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer’s disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC 50 values about 44.67–169.80 nM (donepezil IC 50 50.12 nM). Notably, compound 12 presented potent activities against PDE5A with IC 50 values about 50 μM (sildenafil IC 50 12.59 μM), and some of these compounds showed low cell toxicity to A549 cells in vitro. ]]>