The amyloid state, which is a specific conformation of proteins, offers valuable information about both functional protein structures and the pathological assemblies associated with various diseases. One of the major hallmarks of Alzheimer's disease includes primarily the extracellular build-up of a peptide known as amyloid-β, which has a sequence consisting of 39 to 42 amino acid residues, and the formation of intracellular neurofibrillary tangles mostly consisting of hyperphosphorylated tau protein. Drugs that are expected to reduce Aβ production, prevent Aβ aggregation, and promote Aβ clearance are promising approaches for treating AD. Current work is focused on identifying the compounds that have balanced even mild biological activities against multiple targets instead of finding one-target compound with high potency. We synthesized pregnenolone derivatives and evaluated their potential against inhibition of eeAChE/eqBChE, hCA-II and self-mediated Aβ_1–42 peptide aggregation. Our synthesized derivatives 23, and 25–27 exhibited concomitant inhibition of all the tested macromolecular targets. All the active compounds were found to be BBB penetrants in the PAMPA assay. Furthermore, these selected compounds were found to be non-neurotoxic in the MTT assay on neuroblastoma SH-SY5Y cells. Docking studies support dual binding site (PAS and CAS) inhibition of AChE which showed Aβ_1–42 aggregation and AChE inhibition. Moreover, docking studies carried out on the 3D crystallographic structure of Aβ_1–42 peptide (PDB ID = 1IYT) showed significant interactions with amino acid residues Asp 23 and Lys 28, and hydrophobic interactions with the Phe19, Phe20, and Ala 30 effectively impeding the formation of β-sheet structures.

中文翻译：

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用于治疗阿尔茨海默病的孕烯醇酮衍生物：淀粉样β1-42肽聚集、乙酰胆碱酯酶和碳酸酐酶-II的合成和体外抑制

淀粉样蛋白状态是蛋白质的一种特定构象，它提供了有关功能性蛋白质结构和与各种疾病相关的病理组装的有价值的信息。阿尔茨海默氏病的主要特征之一主要包括一种称为淀粉样蛋白-β 的肽（其序列由 39 至 42 个氨基酸残基组成）的细胞外积聚，以及主要由过度磷酸化 tau 蛋白组成的细胞内神经原纤维缠结的形成。有望减少 Aβ 产生、防止 Aβ 聚集和促进 Aβ 清除的药物是治疗 AD 的有前景的方法。目前的工作重点是鉴定能够平衡多个靶点的温和生物活性的化合物，而不是寻找具有高效力的单一靶点化合物。我们合成了孕烯醇酮衍生物，并评估了它们抑制 eeAChE/eqBChE、hCA-II 和自介导 Aβ _1-42肽聚集的潜力。我们合成的衍生物23和25-27表现出对所有测试的大分子靶标的伴随抑制。在 PAMPA 测定中发现所有活性化合物都是 BBB 渗透剂。此外，在神经母细胞瘤 SH-SY5Y 细胞的 MTT 测定中发现这些选定的化合物无神经毒性。对接研究支持 AChE 的双重结合位点（PAS 和 CAS）抑制，显示 Aβ _1-42聚集和 AChE 抑制。此外，对 Aβ _1-42肽 (PDB ID = 1IYT)的 3D 晶体结构进行的对接研究表明，与氨基酸残基 Asp 23 和 Lys 28 存在显着的相互作用，并且与 Phe19、Phe20 和 Ala 30 的疏水相互作用有效地阻碍了β-折叠结构的形成。