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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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| Authors: | Maalej Emna Chabchoub Fakher Samadi Abdelouahid de los Ríos Cristóbal Perona Almudena Morreale Antonio Marco-Contelles José |
| Institution: | a Laboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et Polymères Faculté des Sciences de Sfax, Université de Sfax, 3018 Sfax, Tunisia b Laboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain c Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817, Alcalá de Henares, Spain d Unidad de Bioinformática, Centro de Biología Molecular Severo Ochoa (CBMSO), Universidad Autónoma de Madrid, Campus de Cantoblanco, C/ Nicolás Cabrera 1, 28049 Madrid, Spain |
| Abstract: | The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo5,6]chromeno2,3-b]quinolin-13-amines (19-28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzof]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-benzo5,6]chromeno2,3-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 Ki 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. |
| Keywords: | AChE BuChE Kinetic analysis Inhibition mechanism Docking analysis Molecular dynamics simulation Alzheimer&rsquo s disease |
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