Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Bioorg Med Chem. 2010 Mar 1;18(5):1749-60. doi: 10.1016/j.bmc.2010.01.071. Epub 2010 Feb 4.
We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.
我们报告了一系列结构上源自多奈哌齐和 AP2238 的杂合化合物。这项研究旨在提高参考化合物多奈哌齐和 AP2238 的活性，并拓宽新衍生物的活性范围，因为由于 AD 的多因素性质，调节单一蛋白靶标活性的分子无法显著改变疾病的进展。特别是，通过双键将多奈哌齐的茚满酮核心与 AP2238 的苯-N-甲基苄基氨基部分连接起来，保持这种较低的灵活性来评估其在生物活性中的作用。此外，还进行了 SAR 研究，以评估茚满酮环 5 或 6 位上不同取代基在与 PAS 相互作用中的作用，同时在一端引入具有不同长度烷基链的不同胺。衍生物 21 和 22 在该系列中表现出最强的活性，它们对 AChE 的活性与参考化合物相当。化合物 15、21-22 带有一个 5 个碳原子的烷基链，一端带有一个氨基部分，更好地与 PAS 接触，显著提高了对 AChE 诱导的 Abeta 聚集的抑制作用，与参考化合物相比。它们还显示出对 Abeta(42)肽自聚集的活性，Abeta(42)肽是 AD 大脑中产生的最具淀粉样的淀粉样蛋白形式，而参考化合物则完全无效。
