title: Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy.
abstract: Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %).
authors.affiliation: Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, BP 802, 3000, Sfax, Tunisia.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Dgachi
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université de Franche-Comté, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 25000, Besançon, France. lhassane.ismaili@univ-fcomte.fr.
authors.forename: Lhassane
authors.initials: L
authors.lastname: Ismaili
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université de Franche-Comté, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 25000, Besançon, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benchekroun
authors.affiliation: Laboratory of Cell Toxicology, EA 4267, University of Franche-Comté, 19 rue Ambroise Paré, 25030, Besançon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Martin
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University, Medical College, Medyczna 9 Street, 30-688, Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.affiliation: Neurosciences Intégratives et Cliniques EA 481, Laboratoire de Chimie Organique et Thérapeutique, UFR SMP, Université de Franche-Comté, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 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 de Franche-Comté, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 25000, Besançon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Luzet
authors.affiliation: Laboratory of Cell Toxicology, EA 4267, University of Franche-Comté, 19 rue Ambroise Paré, 25030, Besançon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bonnet
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University, Medical College, Medyczna 9 Street, 30-688, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.affiliation: Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, BP 802, 3000, Sfax, Tunisia. fakher.chabchoub@yahoo.fr.
authors.forename: Fakher
authors.initials: F
authors.lastname: Chabchoub
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain. iqoc21@iqog.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D008024:Ligands; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007097:Imines; D008024:Ligands; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002802:Cholinesterases
keywords: Alzheimer's disease; antioxidants; inhibitors; molecular modeling; multitarget-directed ligands