title: 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.
abstract: The pharmacological analysis of racemic chromenotacrines (CT) 1-7, 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 μM, 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, CT6 treatment exerts a high protective effect against the lipid peroxidation induced after H₂O₂-treated SH-SY5Y 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) = 0.007 ± 0.003 μM], and CT6 [IC₅₀ (EeAChE) = 0.041 ± 0.001 μM] 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 = 0.047 ± 0.003 μM), 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 CT6 can be considered as an attractive multipotent molecule for the potential treatment of AD.
authors: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain. Electronic address: mjoset@ucm.es.
authors: María Jesús
authors: MJ
authors: Oset-Gasque
authors: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors: María Pilar
authors: MP
authors: González
authors: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors: Javier
authors: J
authors: Pérez-Peña
authors: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors: Nuria
authors: N
authors: García-Font
authors: Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors: Alejandro
authors: A
authors: Romero
authors: Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors: Javier
authors: J
authors: del Pino
authors: Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors: Eva
authors: E
authors: Ramos
authors: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
authors: Dimitra
authors: D
authors: Hadjipavlou-Litina
authors: SEPCO (IQOG, CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
authors: Elena
authors: E
authors: Soriano
authors: Laboratorio de Química Médica (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Mourad
authors: M
authors: Chioua
authors: Laboratorio de Química Médica (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors: Abdelouahid
authors: A
authors: Samadi
authors: Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India.
authors: Dushyant S
authors: DS
authors: Raghuvanshi
authors: Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India. Electronic address: knsinghbhu@yahoo.co.in.
authors: Krishna N
authors: KN
authors: Singh
authors: Laboratorio de Química Médica (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain; Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.
authors: José
authors: J
authors: Marco-Contelles
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control*; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D013237:Stereoisomerism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine
keywords: 11-Amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols; ADMET; Alzheimer's disease; Antioxidant; EeAChE; Inhibition mechanism; Kinetic analysis; Molecular modeling; Neuroprotection; Tacrine analogs; Toxicity; hBuChE