Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor.

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound (BChE IC = 0.18 ± 0.03 μM, BChE IC = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with could almost entirely recover the Aβ (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ total amount confirmed its anti-amyloidogenic profile. Moreover, possessed blood-brain barrier (BBB) penetrating ability, a long , and low intrinsic clearance. Hence, the novel potential BChE inhibitor can be considered as a promising lead compound for further investigation of anti-AD agents.