title: Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids.
abstract: Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.
authors.affiliation: NanoMedicine, Imagery and Therapeutics Lab EA 4662, Laboratoire de Chimie Organique et Thérapeutique, CHRU Jean Minjoz, Université de Franche-Comté, 19, rue Ambroise Paré, 25030 Besançon (France).
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benchekroun
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Elena
authors.initials: E
authors.lastname: Soriano
authors.forename: Marc
authors.initials: M
authors.lastname: Pudlo
authors.forename: Vincent
authors.initials: V
authors.lastname: Luzet
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Jimeno
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.forename: Tijani
authors.initials: T
authors.lastname: Gharbi
authors.forename: Bernard
authors.initials: B
authors.lastname: Refouvelet
authors.forename: Lucía
authors.initials: L
authors.lastname: de Andrés
authors.forename: Clara
authors.initials: C
authors.lastname: Herrera-Arozamena
authors.forename: Barbara
authors.initials: B
authors.lastname: Monti
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Lhassane
authors.initials: L
authors.lastname: Ismaili
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003373:Coumaric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017208:Rats, Wistar; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; D018696:Neuroprotective Agents; D013619:Tacrine; C004999:ferulic acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; antioxidants; cholinesterases; inhibitors; multicomponent reactions; neuroprotection