2026-04-13T18:27:57Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4827382025-04-03T12:06:16Zcom_2072_98col_2072_378192

00925njm 22002777a 4500 dc Pont, Caterina author Sampietro, Anna author Pérez-Areales, F. Javier author Cristiano, Nunzia author Albalat, Agustí author Pérez, Belén author Bartolini, Manuela author De Simone, Angela author Andrisano, Vincenza author Barenys, Marta author Teixido, Elisabet author Sabaté, Raimon author Loza García, María Isabel author Brea, José author Muñoz-Torrero López-Ibarra, Diego author 2024 Altres ajuts: European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan (PRTR-C17.I1), Fundació Bosch i Gimpera, project number 300155; The Autonomous Community of Galicia within the framework of the Biotechnology Plan Applied to Health, and also Xunta de Galicia (ED431C 2022/20) and European Regional Development Fund (ERDF). Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein-huprine hybrid lead by hydroxy group removal-ring contraction-ring opening-ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC » 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification. http://hdl.handle.net/2072/482738 Multitarget drugs Alzheimer's disease Β-amyloid anti-aggregating agents Tau anti-aggregating agents BACE-1 inhibitors Acetylcholinesterase inhibitors Butyrylcholinesterase inhibitors Zebrafish embryos DMPK properties Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties