1. Academic Validation
  2. Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors

Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors

  • Eur J Med Chem. 2019 Nov 1:181:111550. doi: 10.1016/j.ejmech.2019.07.053.
Jesús M Roldán-Peña 1 Valle Romero-Real 1 Javier Hicke 1 Inés Maya 1 Antonio Franconetti 2 Irene Lagunes 3 José M Padrón 3 Sabrina Petralla 4 Eleonora Poeta 4 Marina Naldi 4 Manuela Bartolini 4 Barbara Monti 4 Maria L Bolognesi 4 Óscar López 5 José G Fernández-Bolaños 6
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071, Sevilla, Spain.
  • 2 Department de Química, Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain.
  • 3 BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Apartado 456, E-38071, La Laguna, Spain.
  • 4 Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, via Belmeloro 6, 40126, Bologna, Italy.
  • 5 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071, Sevilla, Spain. Electronic address: osc-lopez@us.es.
  • 6 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071, Sevilla, Spain. Electronic address: bolanos@us.es.
Abstract

Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an Enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aβ42, lacking neurotoxicity up to 5 μM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.

Keywords

Alzheimer's disease; BuChE; Heterodimers; Multitarget; Tacrine.

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