Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor
Qi Li, Shuaishuai Xing, Ying Chen, Ying Chen, Qinghong Liao, Baichen Xiong, Siyu He, Weixuan Lu, Yang Liu, Hongyu Yang, Qihang Li, Feng Feng, Wenyuan Liu, Yao Chen, Yao Chen, Haopeng Sun
Abstract
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 μM, hBChE IC50 = 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. 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 Aβ1–42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ1–42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood–brain barrier (BBB) penetrating ability, a long T1/2, 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.