jm5b00599_si_002.csv (2.43 kB)
Structure-Based Design and Optimization of Multitarget-Directed 2H‑Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases
dataset
posted on 2015-07-23, 00:00 authored by Roberta Farina, Leonardo Pisani, Marco Catto, Orazio Nicolotti, Domenico Gadaleta, Nunzio Denora, Ramon Soto-Otero, Estefania Mendez-Alvarez, Carolina S. Passos, Giovanni Muncipinto, Cosimo
D. Altomare, Alessandra Nurisso, Pierre-Alain Carrupt, Angelo CarottiThe
multifactorial nature of Alzheimer’s disease calls for
the development of multitarget agents addressing key pathogenic processes.
To this end, by following a docking-assisted hybridization strategy,
a number of aminocoumarins were designed, prepared, and tested as
monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE
and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2–12 showed good inhibitory activities at MAO-B, AChE, and BChE but low
selectivity. More rigid inhibitors, bearing meta-
and para-xylyl linkers, displayed good inhibitory
activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring
an improved hydrophilic/lipophilic balance, exhibited excellent activity
profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B
over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based
assays of BBB permeation, neurotoxicity, and neuroprotection supported
the potential of compound 37 as a BBB-permeant neuroprotective
agent against H2O2-induced oxidative stress
with poor interaction as P-gp substrate and very low cytotoxicity.