Search for new multi-target compounds against Alzheimer's disease among histamine H3 receptor ligands.

Abstract

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H3R and both enzymes. Two derivatives were chosen - 5 (IC50 = 0.46 μM (AChE); 0.44 μM (BuChE); Ki = 159.8 nM (H3R)) and 17 (IC50 = 0.50 μM (AChE); 0.76 μM (BuChE); Ki = 228.2 nM (H3R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.

• Authors: Marek Bajda, Dorota Łażewska, Justyna Godyń, Paula Zaręba, Kamil Kuder, Stefanie Hagenow, Kamil Łątka, Ewelina Stawarska, Holger Stark, Katarzyna Kieć-Kononowicz, Barbara Malawska
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 185 Pg. 111785 (Jan 01 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 31669851 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Benzopyrans
• Cholinesterase Inhibitors
• Histamine H3 Antagonists
• Ligands
• Neuroprotective Agents
• Piperidines
• Receptors, Histamine H3
• piperidine
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, metabolism)
• Animals
• Benzopyrans (chemical synthesis, chemistry, pharmacology)
• Butyrylcholinesterase (metabolism)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Electrophorus
• Histamine H3 Antagonists (chemical synthesis, chemistry, pharmacology)
• Horses
• Humans
• Ligands
• Molecular Docking Simulation
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Piperidines (chemical synthesis, chemistry, pharmacology)
• Receptors, Histamine H3 (metabolism)
• Structure-Activity Relationship