丁酰胆碱酯酶
化学
乙酰胆碱酯酶
药效团
变构调节
氨基甲酸酯
立体化学
对接(动物)
酶
IC50型
铅化合物
合理设计
胆碱酯酶
多奈哌齐
有机磷
阿切
组合化学
生物化学
药理学
体外
纳米技术
材料科学
杀虫剂
护理部
病理
生物
医学
疾病
痴呆
农学
作者
Mohammad Shahrivar‐Gargari,Maryam Hamzeh‐Mivehroud,Salar Hemmati,Javid Shahbazi Mojarrad,Tuba Tüylü Küçükkılınç,Beyza Ayazgök,Siavoush Dastmalchi
标识
DOI:10.1002/ardp.202000453
摘要
Inspired by the structures of donepezil and rivastigmine, a novel series of indanone-carbamate hybrids was synthesized using the pharmacophore hybridization-based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 μM; compound 4b: IC50 = 4.64 μM). Moreover, the results of the Aβ1-40 aggregation assay revealed that compound 4b is a potent Aβ1-40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype-selective enzyme inhibitors. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multitargeted anti-Alzheimer agents.
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