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 (IC50=0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ1–42 and pro-oxidant insult. Furthermore, structure–activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.

Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multitarget Ligands Directed towards Relevant Alzheimer's Targets

Purgatorio R.
;
Pisani L.
;
Catto M.;de Candia M.;Carrieri A.;Cellamare S.;De Palma A.;Altomare C. D.
2020-01-01

Abstract

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 (IC50=0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ1–42 and pro-oxidant insult. Furthermore, structure–activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/314856
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