Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach

Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular m...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2016-10, Vol.121, p.758-772
Main Authors: Ceschi, Marco Antonio, da Costa, Jessie Sobieski, Lopes, João Paulo Bizarro, Câmara, Viktor Saraiva, Campo, Leandra Franciscato, Borges, Antonio César de Amorim, Gonçalves, Carlos Alberto Saraiva, de Souza, Daniela Fraga, Konrath, Eduardo Luis, Karl, Ana Luiza Martins, Guedes, Isabella Alvim, Dardenne, Laurent Emmanuel
Format: Article
Language:English
Subjects:
Acetylcholinesterase - chemistry
Acetylcholinesterase - metabolism
AChE
Animals
Brain - drug effects
Brain - enzymology
BuChE
Butyrylcholinesterase - chemistry
Butyrylcholinesterase - metabolism
Catalytic Domain
Chemistry Techniques, Synthetic
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Coupling reaction
Electrophorus
Humans
L-Lactate Dehydrogenase - metabolism
Models, Molecular
Molecular modeling
S100 Calcium Binding Protein beta Subunit - metabolism
S100B secretion
Tacrine
Tacrine - chemistry
Thiazepines - chemical synthesis
Thiazepines - chemistry
Thiazepines - pharmacology
Tianeptine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer’s disease. [Display omitted] •New tacrine-tianeptine hybrids were synthesized.•AChE and BuChE inhibitory activities were performed.•Molecular modeling studies using the X-ray structure of TcAChE.•Two compounds were able to reduce the in vitro basal secretion of S100B.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.06.025