Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer’s Disease

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A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer’s Disease (AD) agents. Among these target compounds, 11a (AChE: IC 50 = 0.048 μM; PDE9A: IC 50 = 0.530 μM) and 11b (AChE: IC 50 = 0.223 μM; PDE9A: IC 50 = 0.285 μM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Aβ 25–35 -induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.