TY - JOUR
T1 - 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
AU - Maalej, Emna
AU - Chabchoub, Fakher
AU - Samadi, Abdelouahid
AU - De Los Ríos, Cristóbal
AU - Perona, Almudena
AU - Morreale, Antonio
AU - Marco-Contelles, José
N1 - Funding Information:
F.C. acknowledges the Ministry of Higher Education, Scientific Research and Technology in Tunisia for financial support. A.S. thanks CSIC for a I3P-post-doc contract. J.M.C. thanks MICINN ( SAF2006-08764-C02-01 ; SAF2009-07271 ), and Comunidad de Madrid ( S/SAL-0275-2006 ) for financial support. C.R.S. thanks Fundación CIEN (ISCIII, MICINN) and Fundación Teófilo Hernando for financial support. The authors thankfully acknowledge the computer resources, technical expertise and assistance provided by the Barcelona Supercomputing Center—Centro Nacional de Supercomputación. A.M. thanks Comunidad de Madrid for BIPPED project financial support. J.M.C. thanks Dr. M. Villarroya, and Prof. L. Gandía (Instituto Teófilo Hernando, Madrid, UAM, Madrid, Spain) for the neuroprotective tests, and for the Ca +2 analyzes, respectively.
PY - 2011/4/15
Y1 - 2011/4/15
N2 - 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 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.
AB - 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 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.
KW - AChE
KW - Alzheimer's disease
KW - BuChE
KW - Docking analysis
KW - Inhibition mechanism
KW - Kinetic analysis
KW - Molecular dynamics simulation
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U2 - 10.1016/j.bmcl.2011.02.094
DO - 10.1016/j.bmcl.2011.02.094
M3 - Article
C2 - 21411323
AN - SCOPUS:79953269221
SN - 0960-894X
VL - 21
SP - 2384
EP - 2388
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 8
ER -