RT Journal Article
T1 8‐Aminomethyl‐7‐hydroxy‐4‐methylcoumarins as Multitarget Leads for Alzheimer's Disease
A1 Domínguez, José L.
A1 Fernández-Nieto, Fernando
A1 Brea Floriani, José Manuel
A1 Catto, Marco
A1 Paleo Pillado, María Rita
A1 Porto, Silvia
A1 Sardina López, Francisco Javier
A1 Castro Pérez, María de los Ángeles
A1 Pisani, Leonardo
A1 Carotti, Angelo
A1 Soto-Otero, Ramón
A1 Méndez Álvarez, Estefanía
A1 Villaverde Cameron-Walker, María del Carmen
A1 Sussman, Fredy Salomon
K1 Alzheimer's disease
K1 8-aminomethyl-7-hydroxy-4-methylcoumarins
K1 Cholinesterases inhibition
K1 Computational chemistry
K1 Drug design
K1 Multitarget leads
AB This work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8‐aminomethyl‐7‐hydroxy‐4‐methyl coumarins as potential multitarget leads for AD. The results of a computer‐assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino‐capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N‐benzylpiperidine fragment, displayed sub‐micromolar affinity for AChE, affinity for BChE, and precluded Aβ‐amyloid aggregation with a potency similar to that of 9,10‐anthraquinone, making it a multitarget lead viable for further improvement
PB Wiley
YR 2016
FD 2016-07-22
LK http://hdl.handle.net/10347/16984
UL http://hdl.handle.net/10347/16984
LA eng
NO Domínguez, J., Fernández-Nieto, F., Brea, J., Catto, M., Paleo, M., & Porto, S. et al. (2016). 8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease. Chemistryselect, 1(11), 2742-2749. doi: 10.1002/slct.201600735
NO This is the peer reviewed version of the following article: Domínguez, J., Fernández-Nieto, F., Brea, J., Catto, M., Paleo, M., & Porto, S. et al. (2016). 8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease. Chemistryselect, 1(11), 2742-2749, which has been published in final form at https://doi.org/10.1002/slct.201600735. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
NO Financial support from the Ministerio de Economia y Competitividad of Spain (Project CTQ2014‐55208‐P) and the Xunta de Galicia (10CSA209063PR and GRC2014/029) is gratefully acknowledged. The Italian authors thank the University of Bari for partial financial support (Fondi di Ateneo 2014–2015)
DS Minerva
RD 30 abr 2026