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.

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defense Trebesska 1575 500 01 Hradec Kralove Czech Republic

Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry Faculty of Pharmacy and Food Science University of Barcelona Av Joan XXIII 27 31 08028 Barcelona Spain Institute of Nanoscience and Nanotechnology University of Barcelona Av Joan XXIII S N 08028 Barcelona Spain

Department of Physicochemical Drug Analysis Faculty of Pharmacy Jagiellonian University Medical College Medyczna 9 30 688 Kraków Poland

Faculty of Pharmacy University of Ljubljana Aškerčeva 7 1000 Ljubljana Slovenia

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