New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

• DOI: 10.1016/j.ejmech.2017.09.022
• Publication Date: 2017-09-19T00:45:40Z
• Authors: 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
• Keywords: Models, Molecular; 0301 basic medicine; Amyloid beta-Peptides; Eels; Dose-Response Relationship, Drug; Molecular Structure; Pyridines; Peptide Fragments; Protein Aggregates; Structure-Activity Relationship; 03 medical and health sciences; Butyrylcholinesterase; Cell Line, Tumor; Acetylcholinesterase; Animals; Humans; acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; amyloid aggregation inhibitors; Cholinesterase Inhibitors; Horses; Cell Proliferation

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.