Design, Synthesis, and Biological Evaluation of 1‑Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer’s Agents

• Published in: ACS chemical neuroscience 2018-05, Vol.9 (5), p.1074-1094
• Main Authors: Panek, Dawid, Więckowska, Anna, Jończyk, Jakub, Godyń, Justyna, Bajda, Marek, Wichur, Tomasz, Pasieka, Anna, Knez, Damijan, Pišlar, Anja, Korabecny, Jan, Soukup, Ondrej, Sepsova, Vendula, Sabaté, Raimon, Kos, Janko, Gobec, Stanislav, Malawska, Barbara
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.7b00461

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer’s disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer’s disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE‑1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer’s agents.