Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of t...

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Detalles Bibliográficos
Autores principales: Bautista-Aguilera, Óscar M., Ismaili, Lhassane, Chioua, Mourad, Andrys, Rudolf, Schmidt, Monika, Bzonek, Petr, Martínez-Grau, María Ángeles, Beadle, Christopher D., Vetman, Tatiana, López-Muñoz, Francisco, Iriepa, Isabel, Refouvelet, Bernard, Musilek, Kamil, Marco-Contelles, José
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312762/
https://www.ncbi.nlm.nih.gov/pubmed/32486316
http://dx.doi.org/10.3390/ijms21113913
Descripción
Sumario:In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC(50) = 0.29 µM), with K(i) value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

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