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.
作者： Emna Maalej , Fakher Chabchoub , Abdelouahid Samadi , Cristóbal de los Ríos , Almudena Perona
DOI: 10.1016/J.BMCL.2011.02.094
关键词: Acetylcholinesterase 、 Chemical synthesis 、 Molecular model 、 Enzyme inhibitor 、 Docking (molecular) 、 Chemistry 、 Tacrine 、 Stereochemistry 、 Selectivity 、 Aryl
摘要: Abstract 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 Friedlander reaction 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], selective inhibitors acetylcholinesterase (AChE). most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-14-yl)phenol (20) (EeAChE) = 7 ± 2 nM] four-fold more active than tacrine. Kinetic studies on compound 20 showed that this a mixed-type inhibitor EeAChE Ki 5.00 nM. However, was unable to displace propidium iodide, suggesting does not strongly bind peripheral anionic site (PAS) AChE. Docking, molecular dynamics stimulations, MM-GBSA calculations agree well behavior.
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