Статья

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

Qi LiSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaShuaishuai XingSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaYing ChenDepartment of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaQinghong LiaoDepartment of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaBaichen XiongSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaSiyu HeState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of ChinaWeixuan LuSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaYang LiuSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaHongyu YangSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaQihang LiSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaFeng FengDepartment of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaWenyuan LiuSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaYao ChenDepartment of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People’s Republic of ChinaHaopeng SunSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China

2020en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1021/acs.jmedchem.0c01129

Цитирования и источники

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