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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

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Oset Gasque, María Jesús and González Prieto, María Pilar and Pérez Peña, Javier and García Font, Nuria and Romero Martínez, Alejandro and Pino Sans, Javier del and Ramos, Eva and Hadjipavlou-Litina, Dimitra and Soriano, Elena and Chioua, Mourad and Samadi, Abdelouahid and Raghuvanshi, Dushyant S. and Singh, Krishna N. and Marco Contelles, José (2014) 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, 74 . pp. 491-501. ISSN 0223-5234

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Official URL: http://dx.doi.org/10.1016/j.ejmech.2013.12.021




Abstract

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.


Item Type:Article
Uncontrolled Keywords:11-Amino-12-aryl-8,9,10,12-tetrahydro-7Hchromeno[2,3-b]quinolin-3-ols, Tacrine analogs, Toxicity, EeAChE hBuChE, Kinetic analysis, Inhibition mechanism, Antioxidant, Neuroprotection, Molecular modeling, ADMET, Alzheimer’s disease
Subjects:Medical sciences > Pharmacy > Biochemistry
ID Code:32457
Deposited On:27 Jul 2015 08:24
Last Modified:04 Aug 2015 10:28

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