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

• Published in: European journal of medicinal chemistry Vol. 54; pp. 750 - 763
• Main Authors: Maalej, Emna, Chabchoub, Fakher, Oset-Gasque, María Jesús, Esquivias-Pérez, Mario, González, María P., Monjas, Leticia, Pérez, Concepción, de los Ríos, Cristóbal, Rodríguez-Franco, María Isabel, Iriepa, Isabel, Moraleda, Ignacio, Chioua, Mourad, Romero, Alejandro, Marco-Contelles, José, Samadi, Abdelouahid
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.08.2012; Elsevier
• Subjects: 7-Aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer's disease; Animals; Antioxidant; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - therapeutic use; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Butyrylcholinesterase - metabolism; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex IV - antagonists & inhibitors; hAChE; hBuChE; Hep G2 Cells; Humans; Inhibition mechanism; Kinetic analysis; Kinetics; Life Sciences & Biomedicine; Models, Molecular; Molecular modeling; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; ORAC; Permeability; Pharmacology & Pharmacy; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Quinolines - therapeutic use; Rats; Reactive Oxygen Species - chemistry; Science & Technology; Stereoisomerism; Toxicity; ORAC; Neuroprotection; 7-Aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines; hBuChE; Toxicity; Molecular modeling; Inhibition mechanism; Kinetic analysis; Antioxidant; Alzheimer's disease; hAChE; TARGET-DIRECTED LIGANDS; RECEPTOR; NO-DONOR; BETA-AMYLOID AGGREGATION; PERIPHERAL SITE; MULTIFUNCTIONAL AGENTS; TACRINE-MELATONIN HYBRIDS; ACETYLCHOLINESTERASE INHIBITORS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.06.038

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. [Display omitted] ► The synthesis, pharmacology and molecular modeling of tacrine analogs 21–30 are described. ► Tacrine 25 [IC50 (hAChE) = 0.33 ± 0.04 μM] is a mixed type inhibitor (Ki = 81 nM). ► Tacrine 25 shows good antioxidant profile (ORAC experiment: 1.47 ± 0.10 Trolox equiv). ► Inhibitors 26–28 and 30 are permeable, neuroprotective and less toxic than tacrine. ► These tacrine analogs are attractive multipotent therapeutic molecules for AD.