Development of tacrine clusters as positively cooperative systems for the inhibition of acetylcholinesterase

Tereza Cristina Santos Evangelista; Óscar López; Sabrina Baptista Ferreira; José G Fernández-Bolaños; Magne O Sydnes; Emil Lindbäck

doi:10.1080/14756366.2021.1954917

Development of tacrine clusters as positively cooperative systems for the inhibition of acetylcholinesterase

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1659-1664. doi: 10.1080/14756366.2021.1954917.

Authors

Tereza Cristina Santos Evangelista^{1

2}, Óscar López³, Sabrina Baptista Ferreira², José G Fernández-Bolaños³, Magne O Sydnes¹, Emil Lindbäck¹

Affiliations

¹ Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway.
² Department of Organic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
³ Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Seville, Spain.

Abstract

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.

Keywords: Acetylcholinesterase; CuAAC; multivalent inhibition potency; multivalent interactions; tacrine.

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Development*
Electrophorus
Molecular Structure
Structure-Activity Relationship
Tacrine / chemical synthesis
Tacrine / chemistry
Tacrine / pharmacology*

Substances

Cholinesterase Inhibitors
Tacrine
Acetylcholinesterase

Grants and funding

This work was supported by the Junta de Andalucía (FQM134), University of Stavanger, Ministerio de Ciencia e Innovación of Spain (MICINN) (CTQ2016-78703-P), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) and European Regional Development Fund (FEDER).