A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

F. Javier Pérez-Areales, Andreea L. Turcu, Marta Barniol-Xicota, Caterina Pont, Deborah Pivetta, Alba Espargaró, Manuela Bartolini, Angela De Simone, Vincenza Andrisano, Belén Pérez, Raimon Sabate, Francesc X. Sureda, Santiago Vázquez, Diego Muñoz-Torrero

Research output: Contribution to journalArticleResearch

9 Citations (Scopus)

Abstract

© 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.
Original languageEnglish
Pages (from-to)613-626
JournalEuropean Journal of Medicinal Chemistry
Volume180
DOIs
Publication statusPublished - 15 Oct 2019

Keywords

  • Acetylcholinesterase inhibitors
  • Brain permeability
  • Butyrylcholinesterase inhibitors
  • Multi-target-directed ligands
  • Multitarget compounds
  • NMDA antagonists

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