Pont, CaterinaGinex, TizianaGriñán Ferré, ChristianScheiner, MatthiasMattellone, AlexiaMartínez, NoemíArce, Elsa M.Soriano Fernández, YolandaNaldi, MarinaSimone, Angela deBarenys, MartaGómez Catalán, JesúsPérez, BelénSabate, RaimonAndrisano, VincenzaLoza García, María IsabelBrea Floriani, José ManuelBartolini, ManuelaBolognesi, Maria LauraDecker, MichaelPallàs, MercèLuque, F. JavierMuñoz Torrero, Diego2026-01-132026-01-132021-06-16Caterina Pont, Tiziana Ginex, Christian Griñán-Ferré, Matthias Scheiner, Alexia Mattellone, Noemí Martínez, Elsa M. Arce, Yolanda Soriano-Fernández, Marina Naldi, Angela De Simone, Marta Barenys, Jesús Gómez-Catalán, Belén Pérez, Raimon Sabate, Vincenza Andrisano, María Isabel Loza, José Brea, Manuela Bartolini, Maria Laura Bolognesi, Michael Decker, Mercè Pallàs, F. Javier Luque, Diego Muñoz-Torrero, From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects, European Journal of Medicinal Chemistry, Volume 225, 2021, 113779, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2021.113779https://hdl.handle.net/10347/45073Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD leadeng© 2021 The Authors. Published by Elsevier Masson SAS. This article is available under the Creative Commons CC-BY-NC-ND licenseAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Alzheimer's diseaseMultitarget compoundCryptic pocketSAMP8Zebrafish embryojournal article10.1016/j.ejmech.2021.1137791768-3254open access