RT Journal Article
T1 Toxicological and pharmacological evaluation, antioxidant, ADMET and molecular modeling of selected racemic chromenotacrines {11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols} for the potential prevention and treatment of Alzheimer’s disease
A1 Oset Gasque, María Jesús
A1 González Prieto, María Del Pilar
A1 Pérez Peña, Javier
A1 García Font, Nuria
A1 Romero Martínez, Manuel Alejandro
A1 Pino Sans, Javier Del
A1 Ramos Alonso, Eva
A1 Hadjipavlou-Litina, Dimitra
A1 Soriano, Elena
A1 Chioua, Mourad
A1 Samadi, Abdelouahid
A1 Raghuvanshi, Dushyant S.
A1 Singh, Krishna N.
A1 Marco Contelles, José Luis
AB The pharmacological analysis of racemic chromenotacrines (CT) 1e7, bearing the 11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol ring skeleton, in a series of experiments targeted to explore their potential use for the treatment of Alzheimer’s disease (AD), is reported. The toxicological evaluation showed that among all these chromenotacrines, CT6 is much less hepatotoxic than tacrine in a range of concentrations from 1 to 300 mM, measured as cell viability in HepG2 cells. Moreover, CT6 did not significantly increase lactate dehydrogenase, aspartate transaminase, and alanine transaminase release in HepG2 cells. Besides,CT6treatment exerts a high protective effect against thelipid peroxidationinduced after H2O2-treated SHSY5Y cells, in a concentration-dependent manner. CT6 showed an excellent antioxidant profile in the AAPH test, and protects against the decrease in cell viability induced by respiratory chain inhibitors (Oligomicyn A/Rotenone)and NO donors in neuronal cultures. This effect could be due to a mixed antiapoptotic and antinecrotic neuroprotective effect at low and intermediate CT6 concentrations, respectively. CT1-7 are potent and selective inhibitors of EeAChE in the submicromolar range. CT3 [IC50 (EeAChE) ¼ 0.007  0.003 mM], and CT6 [IC50 (EeAChE) ¼ 0.041  0.001 mM] are the most potent AChE inhibitors. Kinetic studies on the non-toxic chromenotacrine CT6 showed that this compound behaves as a non-competitive inhibitor (Ki ¼ 0.047  0.003 mM),indicating that CT6 binds at the peripheral anionic site, a fact confirmed by molecular modeling analysis. In silico ADMET analysis showed also that CT6 should have a moderate BBB permeability. Consequently, non-toxic chromenotacrine CT6can be considered as an ttractivemultipotent molecule for the potential treatment of AD.
PB Elsevier
SN 0223-5234
YR 2014
FD 2014-01-08
LK https://hdl.handle.net/20.500.14352/34800
UL https://hdl.handle.net/20.500.14352/34800
LA eng
NO Oset Gasque, M. J., González Prieto, M. P., Pérez Peña, J. et al. «Toxicological and Pharmacological Evaluation, Antioxidant, ADMET and Molecular Modeling of Selected Racemic Chromenotacrines {11-Amino-12-Aryl-8,9,10,12-Tetrahydro-7H-Chromeno[2,3-b]Quinolin-3-Ols} for the Potential Prevention and Treatment of Alzheimer’s Disease». European Journal of Medicinal Chemistry, vol. 74, marzo de 2014, pp. 491-501. DOI.org (Crossref), https://doi.org/10.1016/j.ejmech.2013.12.021.
NO Ministerio de Economía, Comercio y Empresa (España)
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Universidad Complutense de Madrid/Banco de Santander
DS Docta Complutense
RD 21 abr 2025