Cholinesterase inhibitory activity of chlorophenoxy derivatives—Histamine H₃ receptor ligands

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• 作者：Dorota Łażewska^a ; Jakub Jończyk^b ; Marek Bajda^b ; Natalia Szałaj^b ; Anna Więckowska^b ; Dawid Panek^b ; Caitlin Moore^b ; Kamil Kuder^a ; Barbara Malawska^b ; Katarzyna Kieć-Kononowicz^a ; ^{mfkonono@cyr-kr.edu.pl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Acetylcholinesterase inhibitors ; Butyrylcholinesterase inhibitors ; Histamine H3 receptor ; Multifunctional ligands ; Chlorophenoxy derivatives
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：26
• 期：16
• 页码：4140-4145
• 全文大小：1295 K

文摘

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 = 1.93 μM and EqBuChE IC₅₀ = 1.64 μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H₃ receptor as well as with cholinesterases.