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 8012-9656 (eqBChE IC50 = 0.18 +/- 0.03 mu M, hBChE IC50 = 0.32 +/- 0.07 mu M) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 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 8012-9656 could almost entirely recover the A beta(1-42) (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the A beta(1-42) total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T-1/2(,) and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.