Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Chemical Engineering and Biomedical Engineering, University of South Carolina, Columbia, SC 29208, USA.
Int J Mol Sci. 2021 Mar 18;22(6):3120. doi: 10.3390/ijms22063120.
The aggregation of amyloid β (Aβ) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer's disease (AD). Therefore, blocking Aβ aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Aβ aggregation were evaluated using in vitro thioflavin T assays. The structure-activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aβ aggregation and structural modifications on the other parts of the parent molecule (compound ) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Aβ aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD.
淀粉样β（Aβ）肽的聚集和淀粉样斑块的沉积与阿尔茨海默病（AD）的发病机制有关。因此，用小分子阻断 Aβ 聚集被认为是 AD 的一种治疗方法。在本研究中，合成了一系列含有环状酰亚胺等排体的雷尼替丁类似物，并通过体外硫代黄素 T 试验评估了它们对 Aβ 聚集的抑制活性。构效关系表明，1,8-萘酰亚胺部分提供了对 Aβ 聚集的显著抑制，而母体分子（化合物）其他部分的结构修饰保持了相似的功效。其中一些雷尼替丁类似物还具有很强的乙酰胆碱酯酶（AChE）抑制活性，AChE 也是 AD 的另一个治疗靶点。这些雷尼替丁类似物通过针对 Aβ 聚集和 AChE，为治疗 AD 的新型多靶点导向配体的关键化学特征提供了深入了解。
