title: 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.
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 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 [IC(50) (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) [IC(50) (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.
authors.affiliation: Laboratoire de Chimie Appliquée: Hétérocycles, Corps Gras et Polymères Faculté des Sciences de Sfax, Université de Sfax, 3018 Sfax, Tunisia.
authors.forename: Emna
authors.initials: E
authors.lastname: Maalej
authors.forename: Fakher
authors.initials: F
authors.lastname: Chabchoub
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: Almudena
authors.initials: A
authors.lastname: Perona
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology
chemical_list: C559483:4-(13-amino-10,11,12,14-tetrahydro-9H-benzo(5,6)chromeno(2,3-b)quinolin-14-yl)phenol; D000588:Amines; D000634:Aminoquinolines; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine; D000110:Acetylcholinesterase