title: The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.
abstract: Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université Bourgogne Franche-Comté , 19 rue Ambroise Paré, CS 25000 Besançon, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benchekroun
authors.affiliation: Department of Toxicology & Pharmacology, Faculty of Veterinary Medicine, Complutense University of Madrid , E-28040 Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario La Princesa , C/Diego de León 62, E-28006 Madrid, Spain.|Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, E-28029 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario La Princesa , C/Diego de León 62, E-28006 Madrid, Spain.|Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, E-28029 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario La Princesa , C/Diego de León 62, E-28006 Madrid, Spain.|Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, E-28029 Madrid, Spain.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Michalska
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario La Princesa , C/Diego de León 62, E-28006 Madrid, Spain.|Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, E-28029 Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendía
authors.affiliation: Centro Química Orgánica "Lora-Tamayo" (CENQUIOR), CSIC , C/Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Jimeno
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , CZ-500 01 Hradec Kralove, Czech Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove , CZ-500 05 Hradec Kralove, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janockova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , CZ-500 01 Hradec Kralove, Czech Republic.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove , CZ-500 05 Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université Bourgogne Franche-Comté , 19 rue Ambroise Paré, CS 25000 Besançon, France.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Bautista-Aguilera
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université Bourgogne Franche-Comté , 19 rue Ambroise Paré, CS 25000 Besançon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Refouvelet
authors.affiliation: ICR UMR 7273, Aix Marseille University, CNRS , 13013 Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ouari
authors.affiliation: Laboratory of Medicinal Chemistry, IQOG, CSIC , C/Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université Bourgogne Franche-Comté , 19 rue Ambroise Paré, CS 25000 Besançon, France.
authors.forename: Lhassane
authors.initials: L
authors.lastname: Ismaili
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D003373:Coumaric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008550:Melatonin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; D051267:NF-E2-Related Factor 2; C004999:ferulic acid; D002802:Cholinesterases; D008550:Melatonin