New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

Fabiana Pandolfi; Daniela De Vita; Martina Bortolami; Antonio Coluccia; Roberto Di Santo; Roberta Costi; Vincenza Andrisano; Francesco Alabiso; Christian Bergamini; Romana Fato; Manuela Bartolini; Luigi Scipione

doi:10.1016/j.ejmech.2017.09.022

New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

Eur J Med Chem. 2017 Dec 1:141:197-210. doi: 10.1016/j.ejmech.2017.09.022. Epub 2017 Sep 18.

Affiliations

¹ Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Roma, Italy.
² Istituto Pasteur, Fondazione Cenci Bolognetti, Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Roma, Italy.
³ Department for Life Quality Studies, Alma Mater Studiorum University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
⁴ Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6 /Via Irnerio 48, 40126, Bologna, Italy.
⁵ Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6 /Via Irnerio 48, 40126, Bologna, Italy. Electronic address: manuela.bartolini3@unibo.it.
⁶ Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Roma, Italy. Electronic address: luigi.scipione@uniroma1.it.

PMID: 29031067
DOI: 10.1016/j.ejmech.2017.09.022

Abstract

A new series of pyridine derivatives with carbamic or amidic function has been designed and synthesized to act as cholinesterase inhibitors. The synthesized compounds were tested toward EeAChE and hAChE and toward eqBChE and hBChE. The carbamate 8 was the most potent hAChE inhibitor (IC₅₀ = 0.153 ± 0.016 μM) while the carbamate 11 was the most potent inhibitor of hBChE (IC₅₀ = 0.828 ± 0.067 μM). A molecular docking study indicated that the carbamate 8 was able to bind AChE by interacting with both CAS and PAS, in agreement with the mixed inhibition mechanism. Furthermore, the carbamates 8, 9 and 11 were able to inhibit Aβ₄₂ self-aggregation and possessed quite low toxicity against human astrocytoma T67 and HeLa cell lines, being the carbamate 8 the less toxic compound on both cell lines.

Keywords: Acetylcholinesterase inhibitors; Amyloid aggregation inhibitors; Butyrylcholinesterase inhibitors.

MeSH terms

Acetylcholinesterase / metabolism*
Amyloid beta-Peptides / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism
Animals
Butyrylcholinesterase / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Eels
Horses
Humans
Models, Molecular
Molecular Structure
Peptide Fragments / antagonists & inhibitors*
Peptide Fragments / metabolism
Protein Aggregates / drug effects
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Cholinesterase Inhibitors
Peptide Fragments
Protein Aggregates
Pyridines
amyloid beta-protein (1-42)
Acetylcholinesterase
Butyrylcholinesterase
pyridine