Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032, PR China.
Toxicol Appl Pharmacol. 2012 Oct 1;264(1):65-72. doi: 10.1016/j.taap.2012.07.018. Epub 2012 Jul 25.
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.
双结合位点乙酰胆碱酯酶（AChE）抑制与金属螯合的策略可能代表了阿尔茨海默病（AD）病理生理过程中多靶点干预的一个有前途的方向。在本研究中，通过在双（-）-非美他嗪（bis-MEP）的中间链中引入金属螯合药效团，设计并合成了双（-）-非美他嗪（bis-MEP）的两种衍生物（ZLA 和 ZLB）。它们可以抑制人 AChE 活性，IC（50）值分别为 9.63μM（ZLA）和 8.64μM（ZLB），并能抑制 AChE 诱导的淀粉样蛋白-β（Aβ）聚集，IC（50）值分别为 49.1μM（ZLA）和 55.3μM（ZLB）。平行的分子对接分析表明，它们能够与 AChE 的催化和外周阴离子结合位点相互作用。此外，它们还具有与 Cu（II）和 Zn（II）等金属离子络合的能力，并能抑制这些金属引发的 Aβ聚集。总的来说，这些结果表明，ZLA 和 ZLB 可能作为具有金属螯合能力的双结合位点 AChEIs，可能是进一步研究 AD 疾病修饰治疗的有价值的潜在先导化合物。
