Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
Eur J Med Chem. 2016 Aug 25;119:260-77. doi: 10.1016/j.ejmech.2016.04.053. Epub 2016 Apr 26.
In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
在本研究中，设计、合成并评估了一系列三唑并嘧啶-喹啉和氰基吡啶-喹啉杂合体作为乙酰胆碱酯酶抑制剂（AChEIs）。利用分子对接和评分进行抑制剂设计。这些分子是通过一种易于获得的、收敛的合成路线合成的。三种基于三唑并嘧啶的化合物对乙酰胆碱酯酶表现出纳摩尔级的活性。其中，乙基 6-氟-4-（4-（5-甲基-[1,2,4]三唑并[1,5-a]嘧啶-7-基）哌嗪-1-基）喹啉-3-羧酸酯（10d）对乙酰胆碱酯酶的抑制作用最强，IC50 值为 42 nM。此外，化合物 10d 被鉴定为最有前途的化合物，对丁酰胆碱酯酶（BuChE）的选择性是 12 倍。该化合物表现出一种组成性的多靶点特征，对自身诱导和 AChE 诱导的 Aβ聚集具有良好的抑制作用，并具有抗氧化活性。
