Faculty of Pharmacy, Ege-University, Bornova-Izmir, Turkey.
Bioorg Med Chem. 2010 Mar 1;18(5):2049-59. doi: 10.1016/j.bmc.2010.01.002. Epub 2010 Jan 15.
Approved drugs for the treatment of Alzheimer's disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.
用于治疗老年痴呆症的获批药物属于乙酰胆碱酯酶 (AChE) 抑制剂和 NMDA 受体抑制剂这一类。然而，这些药物都无法阻止或逆转疾病的发展。因此，最近报告的有前途的多靶点导向分子方法在这里得到了应用。使用先导化合物 DUO3，它被发现是一种有效的乙酰胆碱酯酶和丁酰胆碱酯酶 (BuChE) 的抑制剂，以及淀粉样蛋白 (Abeta) 斑块形成的抑制剂，合成并生物鉴定了新的非永久性正电荷衍生物。与 DUO3 相反，由于其 pK(a) 值和脂溶性，新的双苯基取代的吡啶亚基腙 5 适合穿过血脑屏障，并抑制乙酰胆碱酯酶和丁酰胆碱酯酶。更重要的是，一些吡啶亚基腙完全抑制 Abeta 纤维的形成，并显著破坏已经形成的纤维。
