TY - JOUR
T1 - Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease
AU - Maalej, Emna
AU - Chabchoub, Fakher
AU - Oset-Gasque, María Jesús
AU - Esquivias-Pérez, Mario
AU - González, María P.
AU - Monjas, Leticia
AU - Pérez, Concepción
AU - De Los Ríos, Cristóbal
AU - Rodríguez-Franco, María Isabel
AU - Iriepa, Isabel
AU - Moraleda, Ignacio
AU - Chioua, Mourad
AU - Romero, Alejandro
AU - Marco-Contelles, José
AU - Samadi, Abdelouahid
N1 - Funding Information:
A. Samadi thanks CSIC for a I3P-post-doc contract. M. Chioua thanks ISCIII for a “Sara Borrell” contract. J. Marco-Contelles thanks MICINN ( SAF2006-08764-C02-01 ; SAF2009-07271 ). JMC (Spain) and Fakher Chabchoub (Tunisia) thank AECID Ministerio de Asuntos Exteriores (Spain) for a grant “Acción Integrada (A1/035457/11)” with Tunisia. F.C. acknowledges the Ministry of Higher Education, Scientific Research and Technology in Tunisia for financial support. M. J. Oset-Gasque thanks MICINN ( SAF2010-20337 ) and UCM-Santander ( GR35/10-B ) for financial support. M. I. Rodríguez-Franco thanks MICINN ( SAF2006-01249 and SAF2009-13015-C02-01 ). L. Monjas thanks the fellowship from Ministerio de Educación y Ciencia (MEC, Spain) for Master Studies. C. de los Ríos thanks ISCIII for a “Miguel Servet” contract ( CP10/00531, ISCIII ), and financial support (Fundación CIEN and “Miguel Servet Program”). JMC thanks Javier Morón-Oset for reading and improving the manuscript.
PY - 2012/8
Y1 - 2012/8
N2 - The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl) -2-methoxyphenol (25), showing a IC50 (hAChE) = 0.33 ± 0.04 μM. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (Ki = 81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 ± 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 μM) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 μM. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease.
AB - The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl) -2-methoxyphenol (25), showing a IC50 (hAChE) = 0.33 ± 0.04 μM. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (Ki = 81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 ± 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 μM) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 μM. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease.
KW - 7-Aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines
KW - Alzheimer's disease
KW - Antioxidant
KW - Inhibition mechanism
KW - Kinetic analysis
KW - Molecular modeling
KW - Neuroprotection
KW - ORAC
KW - Toxicity
KW - hAChE
KW - hBuChE
UR - http://www.scopus.com/inward/record.url?scp=84864405123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864405123&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2012.06.038
DO - 10.1016/j.ejmech.2012.06.038
M3 - Article
C2 - 22795665
AN - SCOPUS:84864405123
SN - 0223-5234
VL - 54
SP - 750
EP - 763
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -