Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids. Issue 3 (23rd December 2014)

• Record Type: Journal Article
• Authors: Benchekroun, Mohamed; Bartolini, Manuela; Egea, Javier; Romero, Alejandro; Soriano, Elena; Pudlo, Marc; Luzet, Vincent; Andrisano, Vincenza; Jimeno, María‐Luisa; López, Manuela G.; Wehle, Sarah; Gharbi, Tijani; Refouvelet, Bernard; de Andrés, Lucía; Herrera‐Arozamena, Clara; Monti, Barbara; Bolognesi, Maria Laura; Rodríguez‐Franco, María Isabel; Decker, Michael; Marco‐Contelles, José; Ismaili, Lhassane
• Is Part Of: ChemMedChem. Volume 10:Issue 3(2015:Mar.)
• Page Start: 523
• Page End: 539
• Publication Date: 2014-12-23
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402409
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>E</italic>)‐3‐(hydroxy‐3‐methoxyphenyl)‐<italic>N</italic>‐{8[(7‐methoxy‐1, 2, 3, 4‐tetrahydroacridin‐9‐yl)amino]octyl}‐<italic>N</italic>‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH <bold>10 n</bold>) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC<sub>50</sub>=68.2 n<sc>M</sc>), 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 <bold>10 n</bold> easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μ<sc>M</sc>), affording good neuroprotection against toxic insults such as Aβ<sub>1–40</sub>, Aβ<sub>1–42</sub>, H<sub>2</sub>O<sub>2</sub>, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μ<sc>M</sc>. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease.</p> </abstract>