Artículo
Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
Autor/es | Roldán Peña, Jesús Miguel
Romero Real, V. Hicke, Javier Maya Castilla, Inés Franconetti García, Antonio Lagunes, Irene Padrón, José M. Petralla, Sabrina Poeta, Eleonora Naldi, Marina Bartolini, Manuela Monti, Barbara Bolognesi, Maria L. López López, Óscar Fernández-Bolaños Guzmán, José María |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2019-11-01 |
Fecha de depósito | 2024-02-05 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia, Innovación y Universidades (MICINN). España Junta de Andalucía European Union (UE) |
Identificador del proyecto | CTQ2016-78703-P
FQM134 501100008530 |
Cita | Roldán Peña, J.M., Romero Real, V., Hicke, J., Maya Castilla, I., Franconetti García, A., Lagunes, I.,...,Fernández-Bolaños Guzmán, J.M. (2019). Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors. European Journal of Medicinal Chemistry, 181, 111550. https://doi.org/10.1016/j.ejmech.2019.07.053. |
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