Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors

作者：Lan, Jin-Shuai; Zhang, Tong; Liu, Yun; Yang, Jing; Xie, Sai-Sai^*; Liu, Jing; Miao, Ze-Yang; Ding, Yue^*

来源：European Journal of Medicinal Chemistry, 2017, 133: 184-196.

DOI：10.1016/j.ejmech.2017.02.045

• Alzheimer's disease
• Donepezil
• Benzylpyridinium
• Acetylcholinesterase inhibitors antioxidant
• beta-Amyloid aggregation
• Neuroprotection

A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced (beta-amyloid (A beta) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of A beta aggregation (53.7% at 20 mu M) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and A beta (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment.

• 出版日期2017-6-16
• 单位上海中医药大学; 江西中医药大学