title: Nontoxic and neuroprotective β-naphthotacrines for Alzheimer's disease.
abstract: The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of β-naphthotacrines1-14 as new drugs for Alzheimer's disease (AD) potential treatment, are reported. β-Naphthotacrines1-14 showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 μM) compounds 7, 10 and 11 displayed 2.25-2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds 10 and 11 in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the β-naphthotacrines bearing electron-donating substituents at the aromatic ring, β-naphthotacrine10 being the most potent (hAChE: IC50 = 0.083 ± 0.024 μM). Kinetic inhibition analysis clearly demonstrated that β-naphthotacrine10 behaves as a mixed-type inhibitor (Ki2= 0.72 ± 0.06 μM) at high substrate concentrations (0.5-10 μM), while at low concentrations (0.01-0.1 μM) it behaves as a hAChE competitive inhibitor (Ki1= 0.007 ± 0.001 μM). These findings identified β-naphthotacrine10 as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment.
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040-Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Esquivias-Pérez
authors.forename: Emna
authors.initials: E
authors.lastname: Maalej
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Fakher
authors.initials: F
authors.lastname: Chabchoub
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Oset-Gasque
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase