TY - JOUR
T1 - Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues
AU - Martins, Carla
AU - Carreiras, M. Carmo
AU - León, Rafael
AU - De Los Ríos, Cristóbal
AU - Bartolini, Manuela
AU - Andrisano, Vincenza
AU - Iriepa, Isabel
AU - Moraleda, Ignacio
AU - Gálvez, Enrique
AU - García, Manuela
AU - Egea, Javier
AU - Samadi, Abdelouhaid
AU - Chioua, Mourad
AU - Marco-Contelles, José
N1 - Funding Information:
Carla Martins thanks Fundação para a Ciência e Tecnologia do Ministério da Ciência, Tecnologia e Ensino Superior of Portugal for her Ph D grant SFRH/BD/17577/2004 . JMC thanks MICINN ( SAF2006-08764-C02-01; SAF2009-07271 ), Comunidad de Madrid ( S/SAL-0275-2006 ), and CSIC-GRICES ( 2007PT-13 ) for financial support.
Funding Information:
MG and JE thank the Spanish Ministry of Science and Innovation Ref. SAF2009-12150 and the Spanish Ministry of Health (Instituto de Salud Carlos III) RETICS-RD06/0026 to MGL. CM thanks COST Action D34 for her STSM, which made possible this collaborative work.
PY - 2011/12
Y1 - 2011/12
N2 - The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines 1-11 and pyrrolotacrine 13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC50 (eqBuChE) = 2.9 ± 0.4 μM; IC50 (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b] quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC50 (EeAChE) = 0.61 ± 0.04 μM; IC50 (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease.
AB - The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines 1-11 and pyrrolotacrine 13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC50 (eqBuChE) = 2.9 ± 0.4 μM; IC50 (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b] quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC50 (EeAChE) = 0.61 ± 0.04 μM; IC50 (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease.
KW - AChE/BuChE inhibitors
KW - Alzheimer's disease
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=80955140466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80955140466&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2011.09.038
DO - 10.1016/j.ejmech.2011.09.038
M3 - Article
C2 - 22000936
AN - SCOPUS:80955140466
SN - 0223-5234
VL - 46
SP - 6119
EP - 6130
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 12
ER -