New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation

• Published in: European journal of medicinal chemistry 2017-12, Vol.141, p.197-210
• Main Authors: Pandolfi, Fabiana, De Vita, Daniela, Bortolami, Martina, Coluccia, Antonio, Di Santo, Roberto, Costi, Roberta, Andrisano, Vincenza, Alabiso, Francesco, Bergamini, Christian, Fato, Romana, Bartolini, Manuela, Scipione, Luigi
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Amyloid aggregation inhibitors; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Butyrylcholinesterase - metabolism; Butyrylcholinesterase inhibitors; 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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.09.022

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. [Display omitted] •A series of pyridine carbamate and amide derivatives was synthesized.•New derivatives acted as dual binding site AChE inhibitors.•The most active compounds inhibit human AChE at submicromolar concentration.•The most interesting derivatives were able to inhibit amyloid self-aggregation.•The best candidate was very low cytotoxic and was predicted to pass the BBB.