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Scouting around 1,2,3,4‐Tetrahydrochromeno[3,2‐ c ]pyridin‐10‐ones for Single‐ and Multitarget Ligands Directed towards Relevant Alzheimer's Targets
Author(s) -
Purgatorio Rosa,
Kulikova Larisa N.,
Pisani Leonardo,
Catto Marco,
Candia Modesto,
Carrieri Antonio,
Cellamare Saverio,
De Palma Annalisa,
Beloglazkin Andrey A.,
Reza Raesi Ghulam,
Voskressensky Leonid G.,
Altomare Cosimo D.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000468
Subject(s) - butyrylcholinesterase , chemistry , reactive oxygen species , monoamine oxidase a , monoamine neurotransmitter , oxidative stress , docking (animal) , aché , ic50 , pharmacology , amyloid precursor protein , cell culture , stereochemistry , biochemistry , monoamine oxidase , alzheimer's disease , disease , enzyme , medicine , biology , in vitro , receptor , acetylcholinesterase , genetics , nursing , serotonin
A number of 1,2,3,4‐tetrahydrochromeno[3,2‐ c ]pyridin‐10‐one derivatives have been synthesized and screened against different targets involved in the onset and progression of Alzheimer's disease (AD), such as acetyl‐ and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of β‐amyloid (Aβ) and reactive oxygen species (ROS) production. Derivatives 1 c , 3 b , 4 and 5 a showed multifaceted profiles of promising anti‐AD features and returned well‐balanced multitargeting inhibitory activities. Moreover, compound 1 f , a potent and selective human MAO B inhibitor (IC 50 =0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH‐SY5Y) by improving viability impaired by Aβ 1–42 and pro‐oxidant insult. Furthermore, structure–activity relationships (SARs) and docking models were derived in order to assist further hit‐to‐lead optimization stage.