TY - JOUR
T1 - Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3- carbonitriles
AU - Samadi, Abdelouahid
AU - Valderas, Carolina
AU - Ríos, Cristóbal De Los
AU - Bastida, Agatha
AU - Chioua, Mourad
AU - González-Lafuente, Laura
AU - Colmena, Inés
AU - Gandía, Luis
AU - Romero, Alejandro
AU - Barrio, Laura Del
AU - Martín-De-Saavedra, María D.
AU - López, Manuela G.
AU - Villarroya, Mercedes
AU - Marco-Contelles, José
N1 - Funding Information:
A. Samadi thanks CSIC for a I3P-post-doc contract. M. Chioua thanks Instituto de Salud Carlos III (MICINN) for a ‘Sara Borrell’ post-doctoral contract. J.M.C. thanks MICINN ( SAF2006-08764-C02-01 , SAF2009-07271 ), ISCIII [Red RENEVAS ( RD06/0026/0009 , RD06/0026/1002 )]), CAM ( S/SAL-0275-2006 ), and CSIC-GRICES ( 2007PT-13 ) financial support. The present work has also been supported by Fundación Teófilo Hernando, MEC Grants BFI2003-02722 , SAF-2006-08540 , SAF2006-1249 and CTQ2005-09365 , and Fundación La Caixa (Barcelona, Spain). L.G. thanks MICINN for support ( SAF 2007-65181 ). M.G.L. thanks MICINN for support ( SAF 2009-12150 ). M.V. thanks Fundación CIEN for support (Instituto de Salud Carlos III). Ágatha Bastida thanks Eva Priego (IQM, CSIC) for the molecular dynamic analysis of compound 16 .
PY - 2011/1/1
Y1 - 2011/1/1
N2 - The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3- carbonitrile (11) [IC50 (EeAChE: 14 nM); IC50 (eqBuChE: 5.2 μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]- naphthyridine-3-carbonitrile (16) [IC50 (EeAChE: 64 nM); IC 50 (eqBuChE: 9.6 μM] showed that this compound is a mixed-type inhibitor (Ki = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K+-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.
AB - The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3- carbonitrile (11) [IC50 (EeAChE: 14 nM); IC50 (eqBuChE: 5.2 μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]- naphthyridine-3-carbonitrile (16) [IC50 (EeAChE: 64 nM); IC 50 (eqBuChE: 9.6 μM] showed that this compound is a mixed-type inhibitor (Ki = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K+-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.
KW - 2-Aminopyridin-3-carbonitriles
KW - AChE
KW - Alzheimer's disease
KW - BuChE
KW - Inhibition mechanism
KW - Molecular modelling
KW - Neuronal cerebrovascular diseases
KW - Neuroprotection
KW - Tacrine analogues
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U2 - 10.1016/j.bmc.2010.11.040
DO - 10.1016/j.bmc.2010.11.040
M3 - Article
C2 - 21163662
AN - SCOPUS:78650757374
SN - 0968-0896
VL - 19
SP - 122
EP - 133
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 1
ER -