Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Department of Pharmacology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Eur J Med Chem. 2022 Mar 5;231:114152. doi: 10.1016/j.ejmech.2022.114152. Epub 2022 Jan 22.
The widespread and the recognition of the multifactorial nature of Alzheimer disease (AD) increased the demands for multi-targeted directed ligands (MTDLs) to overcome possible drug-drug interactions of the combination therapy, and to acquire superior therapeutic profile than single targeted molecules. Two main scaffolds namely: pyrazolopyridine and tetrahydroacridine (THA) were used to synthesize four different series of integrated multi-targeted synthons possessing ChE (hAChE or hBuChE), Aβ aggregation inhibition potency, in addition to optimum metal chelating capability. Structure modifications were performed to 9-amino function of THA core of tacrine and the pyrazolopyridine scaffolds linked to a variety of cyclic secondary amines directly or using amide spacers or ethylamine bridge or engaging THA with pyrazolopyridine to produce hybrid compounds. Different 9-amino substitutions improved the in vitro hAChE activity of 7- or 6,7-disubstituted THA derivatives. Compounds 16 and 28 proved to be multimodal anti-AD agents as they were potent hAChE inhibitors, in addition, they could bind with the amino acids of the peripheral anionic site (PAS) affecting Aβ aggregation and hence Aβ-dependent neurotoxicity especially compound 16 which was almost twofold more active than donepezil. Furthermore, both compounds directly inhibited Aβ self-aggregation and chelated bio-metals such as Fe, Zn and Cu preventing reactive oxygen species (ROS) generation by Aβ and its oxidative damage in the brain regions of AD patients. Compound 28 had superior privilege by its dual ChE activity resulting in better cognitive improvement. Compounds 16 and 28 showed acceptable relative safety upon hepG2 cell line and excellent BBB penetration with wide safety margin as their LD were higher than 120 mg/kg.
阿尔茨海默病（AD）的多因素性质的广泛认识增加了对多靶向定向配体（MTDLs）的需求，以克服组合疗法中可能的药物-药物相互作用，并获得优于单一靶向分子的治疗谱。使用了两种主要骨架，即吡唑并吡啶和四氢吖啶（THA），来合成具有 ChE（hAChE 或 hBuChE）、Aβ 聚集抑制活性以及最佳金属螯合能力的四个不同系列的集成多靶向合成子。对他克林的 THA 核的 9-氨基功能进行了结构修饰，并将吡唑并吡啶骨架直接与各种环状仲胺连接，或者使用酰胺间隔物或乙胺桥连接，或者使 THA 与吡唑并吡啶结合，以产生杂化合物。不同的 9-氨基取代提高了 7-或 6,7-取代 THA 衍生物的体外 hAChE 活性。化合物 16 和 28 被证明是多模式抗 AD 药物，因为它们是有效的 hAChE 抑制剂，此外，它们可以与外周阴离子部位（PAS）的氨基酸结合，影响 Aβ 的聚集，从而影响 Aβ 依赖性神经毒性，特别是化合物 16，其活性几乎是多奈哌齐的两倍。此外，这两种化合物都可以直接抑制 Aβ 自聚集并螯合生物金属，如 Fe、Zn 和 Cu，从而阻止 Aβ 产生的活性氧（ROS）和其在 AD 患者大脑区域的氧化损伤。化合物 28 具有双重 ChE 活性，具有更好的认知改善效果，具有优越的特权。化合物 16 和 28 在 hepG2 细胞系中表现出可接受的相对安全性，并具有良好的 BBB 穿透性和宽的安全裕度，因为它们的 LD 高于 120mg/kg。
