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

• Published in: European journal of medicinal chemistry 2019-11, Vol.181, p.111550, Article 111550
• Main Authors: Roldán-Peña, Jesús M., Romero-Real, Valle, Hicke, Javier, Maya, Inés, Franconetti, Antonio, Lagunes, Irene, Padrón, José M., Petralla, Sabrina, Poeta, Eleonora, Naldi, Marina, Bartolini, Manuela, Monti, Barbara, Bolognesi, Maria L., López, Óscar, Fernández-Bolaños, José G.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; BuChE; Butyrylcholinesterase - metabolism; Cell Proliferation - drug effects; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dimerization; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Electrophorus; Heterodimers; Horses; Humans; Ligands; Models, Molecular; Molecular Structure; Multitarget; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Structure-Activity Relationship; Tacrine; Tacrine - chemical synthesis; Tacrine - chemistry; Tacrine - pharmacology; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.07.053

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. [Display omitted] •A series of tacrine-phenolic hybrids have been accessed as MTDL's for Alzheimer's disease.•Nature/length of the linker (imine, amine, ether) and type of aryl substituents have been modified.•Strong and selective BuChE inhibitors have been obtained (low nanomolar-subnanomolar).•Good Aβ inhibition and neuroprotection profiles were observed.•Low neurotoxicity and hepatotoxicity for the lead compound were observed.