Novel drug-like fluorenyl derivatives as selective butyrylcholinesterase and β-amyloid inhibitors for the treatment of Alzheimer’s disease

• DOI: 10.1016/j.bmc.2023.117333
• Publication Date: 2023-05-18T03:42:11Z
• Authors: Anna Pasieka; Dawid Panek; Paula Zaręba; Emilia Sługocka; Natalia Gucwa; Alba Espargaró; Gniewomir Latacz; Nadia Khan; Adam Bucki; Raimon Sabaté; Anna Więckowska; Barbara Malawska
• Keywords: Butyrylcholinesterase inhibitors; Amyloid beta-Peptides; Molecular Structure; β-amyloid; aggregation; Molecular Dynamics Simulation; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; Alzheimer Disease; Butyrylcholinesterase; Drug Design; Acetylcholinesterase; Humans; Cholinesterase Inhibitors; drug-likeness; Alzheimer’s disease; Fluorene scaffold

Butyrylcholinesterase (BuChE) and amyloid β (Aβ) aggregation remain important biological target and mechanism in the search for effective treatment of Alzheimer's disease. Simultaneous inhibition thereof by the application of multifunctional agents may lead to improvement in terms of symptoms and causes of the disease. Here, we present the rational design, synthesis, biological evaluation and molecular modelling studies of novel series of fluorene-based BuChE and Aβ inhibitors with drug-like characteristics and advantageous Central Nervous System Multiparameter Optimization scores. Among 17 synthesized and tested compounds, we identified 22 as the most potent eqBuChE inhibitor with IC50 of 38 nM and 37.4% of Aβ aggregation inhibition at 10 μM. Based on molecular modelling studies, including molecular dynamics, we determined the binding mode of the compounds within BuChE and explained the differences in the activity of the two enantiomers of compound 22. A novel series of fluorenyl compounds meeting the drug-likeness criteria seems to be a promising starting point for further development as anti-Alzheimer agents.