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Title: A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors
Author: Pérez Areales, Francisco Javier
Turcu, Andreea L.
Barniol-Xicota, Marta
Pont Masanet, Caterina
Pivetta, Deborah
Espargaró Colomé, Alba
Bartolini, Manuela
De Simone, Angela
Andrisano, Vincenza
Pérez, Belén
Sabaté Lagunas, Raimon
Sureda, Francesc X.
Vázquez Cruz, Santiago
Muñoz-Torrero López-Ibarra, Diego
Keywords: Malaltia d'Alzheimer
Malalties neurodegeneratives
Escorça cerebral
Química farmacèutica
Alzheimer's disease
Neurodegenerative Diseases
Cerebral cortex
Pharmaceutical chemistry
Issue Date: 2019
Publisher: Elsevier Masson SAS
Abstract: The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 µM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
Note: Versió postprint del document publicat a:
It is part of: European Journal of Medicinal Chemistry, 2019
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ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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