Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India; Department of Biochemistry I - Receptor Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.
Department of Biochemistry I - Receptor Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.
Eur J Med Chem. 2023 Nov 5;259:115670. doi: 10.1016/j.ejmech.2023.115670. Epub 2023 Jul 24.
Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Aβ) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC = 0.086 μM; 33 - 0.135 μM), and significant Aβ aggregation inhibition (20 μM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC values of 3.00 μM and 2.86 μM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 μM) and HEK-293 cell lines (30 μM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs.
阿尔茨海默病（AD）是一种进行性脑紊乱，与脑功能缓慢丧失有关，导致记忆失败和行为适度改变。这种多因素神经病理学状况是由于胆碱能神经元耗竭和淀粉样β（Aβ）斑块积累引起的。最近，多靶点定向配体（MTDL）策略已成为克服当前挑战的强大药物发现工具。在这项研究工作中，我们旨在设计和开发用于治疗 AD 的三唑桥连芳基金刚烷类似物库。所有合成的类似物都通过各种体外和体内生物学研究进行了表征和评估。最佳化合物 32 和 33 对乙酰胆碱酯酶（AChE）表现出强大的抑制活性（32-IC = 0.086 μM；33-0.135 μM），并且对 Aβ 聚集有显著的抑制作用（20 μM）。在非洲爪蟾卵母细胞中异源表达时，化合物 32 和 33 对 N-甲基-D-天冬氨酸（NMDA）受体（GluN1-1b/GluN2B 亚基组合）的拮抗活性的测量结果表明，其 IC 值分别为 3.00 μM 和 2.86 μM。化合物在 PAMPA 测定中具有良好的血脑屏障通透性，对 SH-SY5Y 神经母细胞瘤（10 μM）和 HEK-293 细胞系（30 μM）安全。此外，在大鼠体内行为研究中，两种化合物在 10 mg/kg 口服给药剂量下均能改善认知和空间记忆障碍。总之，我们的研究结果表明三唑桥连芳基金刚烷是开发抗阿尔茨海默病药物的有前途的新骨架。
