TY - JOUR
T1 - A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors
AU - Pérez-Areales, F. Javier
AU - Turcu, Andreea L.
AU - Barniol-Xicota, Marta
AU - Pont, Caterina
AU - Pivetta, Deborah
AU - Espargaró, Alba
AU - Bartolini, Manuela
AU - De Simone, Angela
AU - Andrisano, Vincenza
AU - Pérez, Belén
AU - Sabate, Raimon
AU - Sureda, Francesc X.
AU - Vázquez, Santiago
AU - Muñoz-Torrero, Diego
PY - 2019/10/15
Y1 - 2019/10/15
N2 - © 2019 Elsevier Masson SAS 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.
AB - © 2019 Elsevier Masson SAS 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.
KW - Acetylcholinesterase inhibitors
KW - Brain permeability
KW - Butyrylcholinesterase inhibitors
KW - Multi-target-directed ligands
KW - Multitarget compounds
KW - NMDA antagonists
U2 - 10.1016/j.ejmech.2019.07.051
DO - 10.1016/j.ejmech.2019.07.051
M3 - Article
C2 - 31351393
VL - 180
SP - 613
EP - 626
ER -