Hariri Roshanak, Afshar Zahra, Mahdavi Mohammad, Safavi Maliheh, Saeedi Mina, Najafi Zahra, Sabourian Reyhaneh, Karimpour-Razkenari Elahe, Edraki Najmeh, Moghadam Farshad Homayouni, Shafiee Abbas, Khanavi Mahnaz, Akbarzadeh Tahmineh
Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.
Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Arch Pharm (Weinheim). 2016 Dec;349(12):915-924. doi: 10.1002/ardp.201600123. Epub 2016 Nov 7.
In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC = 0.37-5.62 μM) compared with rivastigmine (IC = 11.07 μM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.
为了开发有效的抗胆碱酯酶化合物，设计、合成了一系列新型的吡喃并[3',4':5,6]吡喃并[2,3 - b]喹啉酮，并对其进行了体外乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）活性评估。与利伐斯的明（IC = 11.07 μM）相比，所有衍生物均表现出非常好的乙酰胆碱酯酶抑制（AChEI）活性（IC = 0.37 - 5.62 μM）。其中，11 - 氨基 - 12 -（2,3 - 二氯苯基）- 3 - 甲基 - 7,8,9,10 - 四氢吡喃并[3',4':5,6]吡喃并[2,3 - b]喹啉 - 1(12H) - 酮（6f）表现出最佳抑制活性。然而，大多数合成化合物没有抗BChE活性，化合物6b和6f仅为中度抑制剂。最有效的抗AChE化合物6f对β - 分泌酶（BACE1）和氧化应激诱导的细胞死亡分别具有低和中度抑制活性及神经保护作用。此外，结合相互作用的动力学和分子对接研究表明，化合物6f与AChE的催化阴离子位点（CAS）和外周阴离子位点（PAS）均有结合。
