Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands

  • Bioorg Med Chem Lett. 2016 Aug 15;26(16):4140-5. doi: 10.1016/j.bmcl.2016.04.054.
Dorota Łażewska  1 ,  Jakub Jończyk  2 ,  Marek Bajda  2 ,  Natalia Szałaj  2 ,  Anna Więckowska  2 ,  Dawid Panek  2 ,  Caitlin Moore  2 ,  Kamil Kuder  1 ,  Barbara Malawska  2 ,  Katarzyna Kieć-Kononowicz  3
Affiliations
  • 1. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 2. Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 3. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: [email protected].
PMID: 27445168 DOI: 10.1016/j.bmcl.2016.04.054
Abstract

In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both Enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.

Keywords
Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Chlorophenoxy derivatives; Histamine H3 receptor; Multifunctional ligands.
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