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Design, synthesis and biological assessment of new 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) as potential dual inhibitors of acetylcholinesterase and butyrylcholinesterase
Heliyon ( IF 4 ) Pub Date : 2021-04-08 , DOI: 10.1016/j.heliyon.2021.e06683
Samaneh Zarei , Mohammad Shafiei , Maryam Firouzi , Loghman Firoozpour , Kouros Divsalar , Ali Asadipour , Tahmineh Akbarzadeh , Alireza Foroumadi

Alzheimer's disease (AD), is among the most growing neurodegenerative diseases, which is mainly caused by the acetylcholine neurotransmitter loss in the hippocampus and cortex. Emerging of the dual Acetylcholinesterase (AChE)/Butyrylcholinesterase (BuChE) inhibitors has increased for treating Alzheimer disease. In this study, we would like to report the design and synthesis of a new sequence of 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) assessed as BuChE and AChE inhibitors. Ellman's approach was used for the evaluation of AChE and BuChE inhibitory activities. Moreover, docking research was conducted to predict the action mechanism. Among all synthesized compounds, 1-(3-bromobenzyl)-3-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium bromide (BOP-1) was found to be the most active compound with dual activity for inhibition of AChE (IC50 = 5.90 ± 0.07μM), and BuChE (IC50 = 6.76 ± 0.04μM) and 1-(4-chlorobenzyl)-3-((6,7-dimethoxy-4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium chloride (BOP-8) showed the highest AChE inhibitory activity (IC50s = 1.11 ± 0.09 μM). The synthesized compounds BOP-1 and BOP-8 could be proposed as valuable lead compounds for further drug discovery development against AD.



中文翻译:

新的1-苄基-4-((4-氧代喹唑啉-3(4 H)-基)甲基)吡啶-1-鎓衍生物(BOPs)作为乙酰胆碱酯酶和丁酰胆碱酯酶的潜在双重抑制剂的设计,合成和生物学评估

阿尔茨海默氏病(AD)是发展最快的神经退行性疾病之一,主要由海马和皮层中乙酰胆碱神经递质的丧失引起。用于治疗阿尔茨海默氏病的双重乙酰胆碱酯酶(AChE)/丁酰胆碱酯酶(BuChE)抑制剂的出现已经增加。在这项研究中,我们想报告评估的1-苄基-4-((4-氧代喹唑啉-3(4 H)-基)甲基)吡啶-1-鎓衍生物(BOPs)新序列的设计和合成作为BuChE和AChE抑制剂。Ellman方法用于评估AChE和BuChE抑制活性。此外,进行了对接研究以预测作用机理。在所有合成的化合物中,1-(3-溴苄基)-3-((4-氧代喹唑啉-3(4 H)-基)甲基)吡啶-1-溴化铵(BOP-1)被发现是对AChE(IC 50 = 5.90±0.07μM)和BuChE(IC 50 = 6.76± 0.04μM)和1-(4-氯苄基)-3-(((6,7-二甲氧基-4-氧代喹唑啉-3(4 H)-基)甲基)吡啶基]氯化铵(BOP-8)最高AChE抑制活性(IC 50 s = 1.11±0.09μM)。合成的化合物BOP-1和BOP-8可以作为有价值的先导化合物用于进一步开发针对AD的药物。

更新日期:2021-04-08
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