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

Marco Antonio Ceschi; Jessie Sobieski da Costa; João Paulo Bizarro Lopes; Viktor Saraiva Câmara; Leandra Franciscato Campo; Antonio César de Amorim Borges; Carlos Alberto Saraiva Gonçalves; Daniela Fraga de Souza; Eduardo Luis Konrath; Ana Luiza Martins Karl; Isabella Alvim Guedes; Laurent Emmanuel Dardenne

doi:10.1016/j.ejmech.2016.06.025

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

Eur J Med Chem. 2016 Oct 4:121:758-772. doi: 10.1016/j.ejmech.2016.06.025. Epub 2016 Jun 23.

Affiliations

¹ Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970, Porto Alegre, RS, Brazil. Electronic address: [email protected].
² Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970, Porto Alegre, RS, Brazil.
³ Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio Anexo, 90035-003, Porto Alegre, RS, Brazil.
⁴ Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av Ipiranga, 2752, Santana, 90610000, Porto Alegre, RS, Brazil.
⁵ Laboratório Nacional De Computação Científica-LNCC, Av. Getulio Vargas, 333, Petrópolis, 25651-075, RJ, Brazil.
⁶ Laboratório Nacional De Computação Científica-LNCC, Av. Getulio Vargas, 333, Petrópolis, 25651-075, RJ, Brazil. Electronic address: [email protected].

PMID: 27392529
DOI: 10.1016/j.ejmech.2016.06.025

Abstract

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.

Keywords: AChE; BuChE; Coupling reaction; Molecular modeling; S100B secretion; Tacrine; Tianeptine.

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Animals
Brain / drug effects
Brain / enzymology
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Catalytic Domain
Chemistry Techniques, Synthetic
Cholinesterase Inhibitors / chemistry*
Cholinesterase Inhibitors / pharmacology*
Electrophorus
Humans
L-Lactate Dehydrogenase / metabolism
Models, Molecular
S100 Calcium Binding Protein beta Subunit / metabolism
Tacrine / chemistry*
Thiazepines / chemical synthesis
Thiazepines / chemistry*
Thiazepines / pharmacology*

Substances

Cholinesterase Inhibitors
S100 Calcium Binding Protein beta Subunit
Thiazepines
tianeptine
Tacrine
L-Lactate Dehydrogenase
Acetylcholinesterase
Butyrylcholinesterase