Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives.
Acetylcholinesterase
/ chemistry
Adjuvants, Anesthesia
/ toxicity
Alzheimer Disease
/ drug therapy
Amnesia
/ chemically induced
Animals
Butyrylcholinesterase
/ chemistry
Cholinesterase Inhibitors
/ chemistry
Computational Biology
Disease Models, Animal
In Vitro Techniques
Ligands
Male
Mice
Models, Molecular
Molecular Structure
Piperazines
/ chemistry
Receptors, Histamine H3
/ chemistry
Scopolamine
/ toxicity
Structure-Activity Relationship
Acetylcholinesterase
Alzheimer’s disease
Butyrylcholinesterase
Cholinesterase inhibitors
H3 histamine receptor
Multi-target-directed ligands
Piperazine
Thiazole
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
11
02
2019
revised:
24
05
2019
accepted:
24
06
2019
pubmed:
5
7
2019
medline:
21
10
2020
entrez:
5
7
2019
Statut:
ppublish
Résumé
In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA
Identifiants
pubmed: 31271942
pii: S0045-2068(19)30228-7
doi: 10.1016/j.bioorg.2019.103084
pii:
doi:
Substances chimiques
Adjuvants, Anesthesia
0
Cholinesterase Inhibitors
0
Ligands
0
Piperazines
0
Receptors, Histamine H3
0
Scopolamine
DL48G20X8X
Acetylcholinesterase
EC 3.1.1.7
Butyrylcholinesterase
EC 3.1.1.8
Types de publication
Evaluation Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103084Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.