Department of Persian Medicine, School of Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Sci Rep. 2024 Sep 10;14(1):21115. doi: 10.1038/s41598-024-71729-0.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, H NMR, and C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe. The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响着全球的老年人群体，因此迫切需要开发新型的抗 AD 药物。在本研究中，设计并合成了一系列新的吲哚异噁唑甲脒。采用包括 FTIR、H NMR、C NMR 以及质谱和元素分析在内的光谱方法阐明了所有化合物的结构。对所有衍生物进行了乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制活性筛选。在所合成的所有化合物中，化合物 5d 作为 AChE 抑制剂表现出最高的活性，IC 值为 29.46 ± 0.31 μM。它对 AChE 具有显著的选择性，对 BuChE 没有明显的抑制作用。对化合物 5d 的 AChE 的动力学研究表明，其抑制模式为竞争性抑制。此外，5d 对 BACE1 具有有希望的抑制潜力，IC 值为 2.85 ± 0.09 μM，并且具有体外金属螯合能力，能够与 Fe 结合。还对 5d 针对 AChE 和 BACE1 的分子动力学进行了研究，以评估该衍生物在结合部位的行为。结果表明，新化合物值得进一步的化学优化，以考虑作为潜在的抗 AD 药物。
