Karami Hosna, Soltani Somaieh, Wolber Gerhard, Sadigh-Eteghad Saeed, Nikbakht Roghaye, Farrokhi Hanieh, Narimani Farzaneh, Teimuri-Mofrad Reza, Rashidi Mohammad-Reza
Higher Education Institute of Rab-Rashid, Tabriz, Iran.
Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran.
Bioimpacts. 2024 Dec 29;15:24196. doi: 10.34172/bi.24196. eCollection 2025.
Multi-target anti-Alzheimer's disease (AD) compounds are promising leads for the development of AD modifying agents. Ionic compounds containing quaternary ammonium moiety were synthesized, and their multi-targeted anti-AD effects were examined.
Imidazole derivatives containing a quaternary ammonium moiety were synthesized and evaluated for their potential anti-Alzheimer properties using computational (), cellular (), and animal () models. The inhibition kinetics of both human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) were assessed. Neuroprotective effects in amyloid-beta (Aβ)-exposed PC12 cells were also examined. Furthermore, the compounds' impact on Aβ-induced memory impairment in Wistar rats was evaluated, with a detailed analysis of the underlying mechanisms.
Compound 5g demonstrated acceptable cytotoxicity against human cells. This compound exhibited non-competitive dual inhibition of both hAChE and hBuChE. Additionally, compound 5g mitigated the morphological changes induced by amyloid-beta (Aβ) in PC12 cells and decreased cell mortality. It exhibited anti-oxidative stress properties, evident by reduction in reactive oxygen species (ROS) production, and inhibition of lipid peroxidation. The compound also down regulated the expression of pro-inflammatory genes IL-1β and TNF-α. In vitro studies validated compound 5g's ability to inhibit lactate dehydrogenase (LDH), attenuate neuroinflammation, and prevent the autophagy-apoptosis cascade. When administered to rats with Aβ-induced memory dysfunction, compound 5g enhanced cognitive function and improved spatial memory. In the hippocampi of treated rats, there was a noted downregulation of TNF-α and NF-kB. Furthermore, compound 5g counteracted the elevated activity of AChE. Molecular modeling validated the binding of compound 5g to both steric and catalytic sites of cholinesterase enzymes.
The novel quaternary ammonium derivative, compound 5g, demonstrated multi-target anti-AD properties, as evidenced by and studies. Behavioral assessments and molecular analyses further confirmed its therapeutic efficacy in amyloid-beta (Aβ)-challenged rats.
多靶点抗阿尔茨海默病（AD）化合物是开发AD修饰剂的有前景的先导化合物。合成了含季铵部分的离子化合物，并研究了它们的多靶点抗AD作用。
合成了含季铵部分的咪唑衍生物，并使用计算（）、细胞（）和动物（）模型评估其潜在的抗阿尔茨海默病特性。评估了人乙酰胆碱酯酶（hAChE）和丁酰胆碱酯酶（hBuChE）的抑制动力学。还研究了化合物对淀粉样β蛋白（Aβ）处理的PC12细胞的神经保护作用。此外，评估了这些化合物对Wistar大鼠Aβ诱导的记忆损伤的影响，并详细分析了其潜在机制。
化合物5g对人细胞表现出可接受的细胞毒性。该化合物对hAChE和hBuChE均表现出非竞争性双重抑制作用。此外，化合物5g减轻了Aβ诱导的PC12细胞形态变化并降低了细胞死亡率。它表现出抗氧化应激特性，表现为活性氧（ROS）产生减少和脂质过氧化受到抑制。该化合物还下调了促炎基因IL-1β和TNF-α的表达。体外研究证实了化合物5g抑制乳酸脱氢酶（LDH）、减轻神经炎症和防止自噬-凋亡级联反应的能力。当给予Aβ诱导的记忆功能障碍大鼠时，化合物5g增强了认知功能并改善了空间记忆。在治疗大鼠的海马中，TNF-α和NF-κB明显下调。此外，化合物5g抵消了AChE活性的升高。分子建模验证了化合物5g与胆碱酯酶的空间和催化位点的结合。
新型季铵衍生物化合物5g表现出多靶点抗AD特性， 和 研究证明了这一点。行为评估和分子分析进一步证实了其在Aβ攻击大鼠中的治疗效果。
