Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 180, Issue -, Pages 613-626Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.07.051
Keywords
Multitarget compounds; Multi-target-directed ligands; Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; NMDA antagonists; Brain permeability
Categories
Funding
- Ministerio de Ciencia, Innovacion y Universidades, Agencia Estatal de Investigacion (AEI)
- FEDER [SAF2017-82771-R]
- Generalitat de Catalunya (GC) [2017SGR106]
- Ministerio de Educacion, Cultura y Deporte
- Lifelong Learning Programme/Erasmus
- Juan de la Cierva program of Ministerio de Economia y Competitividad [JCI-2012-12193]
- GC
Ask authors/readers for more resources
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 mu M 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available