1 research outputs found
Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
Through
drug discovery strategies of repurposing and redeveloping
existing drugs, a series of novel tadalafil derivatives were rationally
designed, synthesized, and evaluated to seek dual-target AChE/PDE5
inhibitors as good candidate drugs for Alzheimer’s disease
(AD). Among these derivatives, <b>1p</b> and <b>1w</b> exhibited excellent selective dual-target AChE/PDE5 inhibitory activities
and improved blood-brain barrier (BBB) penetrability. Importantly, <b>1w·Cit</b> (citrate of <b>1w</b>) could reverse the
cognitive dysfunction of scopolamine-induced AD mice and exhibited
an excellent effect on enhancing cAMP response element-binding protein
(CREB) phosphorylation in vivo, a crucial factor in memory formation
and synaptic plasticity. Moreover, the molecular docking simulations
of <b>1w</b> with hAChE and hPDE5A confirmed that our design
strategy was rational. In summary, our research provides a potential
selective dual-target AChE/PDE5 inhibitor as a good candidate drug
for the treatment of AD, and it could also be regarded as a small
molecule probe to validate the novel AD therapeutic approach in vivo