title: Novel bis-(-)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property.
abstract: The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(-)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC(50) values of 9.63μM (for ZLA) and 8.64μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC(50) values of 49.1μM (for ZLA) and 55.3μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD.
authors: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032, PR China.
authors: Wei
authors: W
authors: Zheng
authors: Juan
authors: J
authors: Li
authors: Zhuibai
authors: Z
authors: Qiu
authors: Zheng
authors: Z
authors: Xia
authors: Wei
authors: W
authors: Li
authors: Lining
authors: L
authors: Yu
authors: Hailin
authors: H
authors: Chen
authors: Jianxing
authors: J
authors: Chen
authors: Yan
authors: Y
authors: Chen
authors: Zhuqin
authors: Z
authors: Hu
authors: Wei
authors: W
authors: Zhou
authors: Biyun
authors: B
authors: Shao
authors: Yongyao
authors: Y
authors: Cui
authors: Qiong
authors: Q
authors: Xie
authors: Hongzhuan
authors: H
authors: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002614:Chelating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008621:Meptazinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D015032:Zinc / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; C583419:bis(9)-normeptazinol; D008621:Meptazinol; D003300:Copper; D000110:Acetylcholinesterase; D015032:Zinc