Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines

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• 作者：Emna Maalej^a ; ; Fakher Chabchoub^a ; ^{fakher.chabchoub@yahoo.fr} ; Abdelouahid Samadi^b ; Cristó ; bal de los Rí ; os^c ; Almudena Perona^d ; Antonio Morreale^d ; José ; Marco-Contelles^b ; ^{iqoc21@iqog.csic.es}
• 关键词：AChE ; BuChE ; Kinetic analysis ; Inhibition mechanism ; Docking analysis ; Molecular dynamics simulation ; Alzheimer’ ; s disease
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 April 2011
• 年：2011
• 卷：21
• 期：8
• 页码：2384-2388
• 全文大小：546 K

文摘

The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines (19–28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles (10–18) with suitable cycloalkanones is described. These molecules are potent, in the nanomolar range [IC₅₀ (EeAChE) = 7–101 nM], and selective inhibitors of acetylcholinesterase (AChE). The most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-14-yl)phenol (20) [IC₅₀ (EeAChE) = 7 ± 2 nM] is four-fold more active than tacrine. Kinetic studies on compound 20 showed that this is a mixed-type inhibitor of EeAChE with a K_i of 5.00 nM. However, racemic 20 was unable to displace propidium iodide, suggesting that the inhibitor does not strongly bind to the peripheral anionic site (PAS) of AChE. Docking, molecular dynamics stimulations, and MM-GBSA calculations agree well with this behavior.