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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.
Pont Masanet, Caterina
Espargaró Colomé, Alba
De Simone, Angela
Sabaté Lagunas, Raimon
Sureda, Francesc X.
Vázquez Cruz, Santiago
Muñoz-Torrero López-Ibarra, Diego
|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: https://doi.org/10.1016/j.ejmech.2019.07.051|
|It is part of:||European Journal of Medicinal Chemistry, 2019|
|Appears in Collections:||Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)|
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