Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

Ornella Di Pietro, F. Javier Pérez-Areales, Jordi Juárez-Jiménez, Alba Espargaró, M. Victòria Clos, Belén Pérez, Rodolfo Lavilla, Raimon Sabaté, F Javier Luque, Diego Muñoz-Torrero

Research output: Contribution to journalArticlepeer-review


Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c] quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC 50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.

Original languageEnglish
Pages (from-to)107-117
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Early online date7 Jul 2014
Publication statusPublished - 12 Sep 2014


  • Aβ aggregation inhibitors
  • Dual binding site AChE inhibitors
  • Multitarget compounds
  • Tau aggregation inhibitors
  • Tetrahydrobenzo[h][1,6]naphthyridines


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