新型 2-苯并[b][1,4]噻嗪-3(4H)-酮衍生物的设计、合成与乙酰胆碱酯酶抑制活性评价。

Design, Synthesis, and Evaluation of Novel 2-Benzo[b][1,4]thiazin-3(4)-one Derivatives as New Acetylcholinesterase Inhibitors.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hawler Medical University, Erbil 44000, Iraq.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Turkey.

出版信息

Molecules. 2022 Mar 25;27(7):2121. doi: 10.3390/molecules27072121.

DOI:10.3390/molecules27072121

PMID:35408519

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9000418/

Abstract

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds and displayed significant inhibitory activity against AChE. Compounds and showed IC values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds ( and ) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds and exhibited greater antioxidant effects. An in vitro blood-brain barrier permeability study showed that compounds and are promising compounds against AD. The cytotoxicity study of compounds and showed non-cytotoxic with an IC value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively.

摘要

阿尔茨海默病（AD）是一种缓慢进展的神经退行性疾病，导致 65 岁及以上人群痴呆。在本研究中，开发了一系列噻二唑杂合化合物，其苯并噻嗪衍生物作为乙酰胆碱酯酶抑制剂，并对其生物活性进行了评价。所有化合物的 AChE 和 BChE 抑制潜力均通过体外 Ellman 法进行评估。生物评价表明，化合物和对 AChE 表现出显著的抑制活性。化合物和对 AChE 的 IC 值分别为 0.027 µM 和 0.025 µM。参考药物多奈哌齐（IC = 0.021 µM）也对 AChE 表现出显著抑制作用。进一步的对接模拟也表明，这些化合物（和）与酶的活性位点相互作用类似于多奈哌齐。抗氧化研究表明，化合物和表现出更强的抗氧化作用。体外血脑屏障通透性研究表明，化合物和是有希望的 AD 治疗药物。化合物和的细胞毒性研究显示非细胞毒性，对 NIH/3T3 细胞的 IC 值分别为 98.29 ± 3.98 µM 和 159.68 ± 5.53 µM。