Journal of Medicinal Chemistry p. 5561 - 5578 (2015)
Update date:2022-08-15
Topics:
Farina, Roberta
Pisani, Leonardo
Catto, Marco
Nicolotti, Orazio
Gadaleta, Domenico
Denora, Nunzio
Soto-Otero, Ramon
Mendez-Alvarez, Estefania
Passos, Carolina S.
Muncipinto, Giovanni
Altomare, Cosimo D.
Nurisso, Alessandra
Carrupt, Pierre-Alain
Carotti, Angelo
The 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.
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Doi:10.1021/jp910615y
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