American Chemical Society
jm0c00528_si_010.pdb (661.93 kB)

Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR‑6

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posted on 2020-08-11, 18:50 authored by F. Javier Pérez-Areales, María Garrido, Ester Aso, Manuela Bartolini, Angela De Simone, Alba Espargaró, Tiziana Ginex, Raimon Sabate, Belén Pérez, Vincenza Andrisano, Dolors Puigoriol-Illamola, Mercè Pallàs, F. Javier Luque, María Isabel Loza, José Brea, Isidro Ferrer, Francisco Ciruela, Angel Messeguer, Diego Muñoz-Torrero
Oxidative stress is a major pathogenic factor in Alzheimer’s disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aβ42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.