Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

• DOI: 10.1002/cmdc.201402409
• Publication Date: 2014-12-23T22:16:58Z
• Authors: Mohamed Benchekroun; Manuela Bartolini; Javier Egea; Alejandro Romero; Elena Soriano; Marc Pudlo; Vincent Luzet; Vincenza Andrisano; María‐Luisa Jimeno; Manuela G. López; Sarah Wehle; Tijani Gharbi; Bernard Refouvelet; Lucía de Andrés; Clara Herrera‐Aro...; Barbara Monti; Maria Laura Bolog...; María Isabel Rodr...; Michael Decker; José Marco‐Contelles; Lhassane Ismaili
• Keywords: Tacrine; Trolox; Butyrylcholinesterase; Viability assay

Abstract Herein we describe the design, multicomponent synthesis, and biological, molecular modeling ADMET studies, as well 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}‐ ‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n ) a particularly interesting multipotent compound that shows moderate completely selective inhibition human butyrylcholinesterase (IC 50 =68.2 M ), strong antioxidant activity (4.29 equiv trolox an oxygen radical absorbance capacity (ORAC) assay), good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, determined by PAMPA‐BBB assay. Notably, even when tested very high concentrations, TFAH easily surpasses other TFAHs hepatotoxicity profiling (59.4 cell viability 1000 μ affording neuroprotection against toxic insults such Aβ 1–40 , 1–42 H 2 O oligomycin A/rotenone on SH‐SY5Y cells, 1 . The results reported herein support development derivatives potential drugs for treatment Alzheimer′s disease.