2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents

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

  • ACS Chem Neurosci. 2018 May 16;9(5):1074-1094. doi: 10.1021/acschemneuro.7b00461.
Dawid Panek 1,  Anna Więckowska 1,  Jakub Jończyk 1,  Justyna Godyń 1,  Marek Bajda 1,  Tomasz Wichur 1,  Anna Pasieka 1,  Damijan Knez 2,  Anja Pišlar 2,  Jan Korabecny 3 4,  Ondrej Soukup 3 4,  Vendula Sepsova 3 4,  Raimon Sabaté 5 6,  Janko Kos 2,  Stanislav Gobec 2,  Barbara Malawska 1
Affiliations

Affiliations

  • 1 Department of Physicochemical Drug Analysis, Faculty of Pharmacy , Jagiellonian University Medical College , Medyczna 9 , 30-688 Kraków , Poland.
  • 2 Faculty of Pharmacy , University of Ljubljana , Aškerčeva 7 , 1000 Ljubljana , Slovenia.
  • 3 Biomedical Research Centre , University Hospital Hradec Kralove , Sokolska 581 , 500 05 Hradec Kralove , Czech Republic.
  • 4 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences , University of Defense , Trebesska 1575 , 500 01 Hradec Kralove , Czech Republic.
  • 5 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.
  • 6 Institute of Nanoscience and Nanotechnology (IN2UB) , University of Barcelona , Av Joan XXIII, S/N , 08028 Barcelona , Spain.
PMID: 29345897 DOI: 10.1021/acschemneuro.7b00461
Abstract

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.

Keywords

Alzheimer’s disease; Aβ aggregation; BACE-1 inhibitors; butyrylcholinesterase inhibitors; molecular docking; multifunctional agents; tau aggregation.

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